Sergio Cesaratto

Agency, functionalism, and all that. A Sraffian view

Keywords: agency, functionalism, organicism, historical materialism, surplus approach

Former contributions examined the approach to institutions and economic history that can be derived from the classical and Marxian 'surplus approach'. The present paper deals with the allegation levelled against historical materialism of organicism or functionalism. Organicism is said to look at individuals as passive vectors functionally serving in various capabilities the reproduction and destiny of society as a whole. In this way human agency in the operation and change of society is excluded or at least restrained. Methodological individualism is the traditional alternative supported both by neoclassical and by (some) Marxist schools. The literature over the 'agency versus structure' determination of human behaviour in social and human sciences is immense. Therefore, I limited myself to some authors that I deemed more appropriate in relation to the application of the classical surplus approach to institutions and economic history. I shall defend a functionalist view of society while giving space to individual intentional action and aspirations, albeit informed by historical conditioning circumstances. Historical reconstruction of the objective and subjective features of the economic formations under examination, rather than the empty and a-historical study of individual choices, unrelated to the social context, looks like the way to go. Agency must be historically contextualised.

Introduction

The issue whether human beings enjoy real freedom of choice, or their behaviour is ultimately conditioned by a host of biological, social, and cultural relations were embedded in a variety of historical personal and political connections regulating the extraction of the social surplus from labour that took the general economic form of pre-capitalist ground rent [START_REF] Haldon | The State and the Tributary Mode of Production[END_REF].

By way of recovering the classical surplus approach 'submerged and forgotten' since the 'advent of the "marginal" method"' (Sraffa 1960, p. v), and in continuity with Marx, in 1931 Sraffa was well aware that 'the economic field' was not autonomous from the social and institutional context, writing, for instance, that 'the surplus may be the effect of outside causes' (quoted by Ginzburg 2015, p. 64). As [START_REF] Davis | The change in Sraffa's philosophical thinking[END_REF]Davis ( , p. 1353) put it, Sraffa's 'objectivism is a subtle one in that it both preserves a physical basis for the world of production and at the same time shows it to be influenced by a social activity that operates upon and within it' (see also [START_REF] Davis | Sraffa on the open vs. "closed systems" distinction and causality[END_REF]).

Sraffa's and Garegnani's work make it possible to state, on a more solid basis than does the labour theory of value that Marx borrowed from Ricardo, that in capitalism the dominant class appropriate a share of the social product on the mere basis of the prevailing social order, no less than in pre-capitalist economies -where this is generally acknowledged, obtorto collo, even by marginalist economists. On the role of the labour theory of value in classical economics and for a response to Sraffa's critics I refer to [START_REF] Garegnani | On the labour theory of value in Marx and in the Marxist tradition[END_REF]. We can observe here in passing that in pre-capitalist economies, for Marx it is indifferent whether the agrarian rent is extracted as the appropriation of part of the working day (in the form of corvee on owner's land) or as a physical part of the product (sharecropping).

While Sraffa revived, in my opinion, the economic core of Marx's thought, historical materialism is not without problems which a century and a half of Marxist debates has brought to light. Within a possibly much longer list, I envisage two specific questions [START_REF] Cesaratto | Schools of Athens: surplus approach, Marxism and institutions[END_REF]).

To begin with, Marx's idea of a strict relation, roughly expressed, between specific historical forms of extraction and distribution of the social surplus and the accompanying institutions, both defining a given socio-economic formation, is essentially sound and robust (and it has even become commonsensical in social sciences). However, the dynamic of change of socio-economic formations is less clear. Simplifying, Marx deemed the clash between an evolving production base of the economy (forces of production) and a dominant social superstructure Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

The Journal of Philosophical Economics XVII (Annual issue) 2024 51

(relations of production) as the trigger of institutional change. In this view, either a change in production techniques appears as the ultimate driver, the deus ex machina of history; or tensions within the relations of production pave the way to those changes. A clarification of the dynamic interaction between material and institutional change is still badly needed. In this regard, Ginzburg (2015, p. 61) recalls Gramsci's reproach of Bukharin's scientistic and mechanistic Marxism that would avoid the fundamental question of 'how does the historical movement arise out from the structures?' To solve this 'crucial point of all historical materialism' Gramsci refers to political subjectivity (the Party) as the lever of change -leveraging, of course, material forces.

In this paper this issue will be dealt with in the context of a second, more general question concerning the allegation levelled against historical materialism, and consequently against the surplus approach to institutions, of organicism or functionalism. Organicism would look at individuals as passive vectors functionally serving, through the mediation of social groups and institutions, deeper socio-economic forces and interests. In this way any human agency in the working and, more importantly, change of society would be excluded or at least confined. (Remarkably, this topic is thus relevant also for the first issue, that of the dynamics of change [2].) Notably, criticism to Marxism for neglecting individual or class subjectivism in favour of objectivism has also come from within Marxism itself, and roughly overlaps with the clash between so-called historicists and structuralists [START_REF] Cesaratto | Schools of Athens: surplus approach, Marxism and institutions[END_REF]). Methodological individualism is the traditional alternative to organicist theories supported both by neoclassical and by (some) Marxist schools.

The debate over the 'agency versus structure' determination of human behaviour in social sciences and humanities is limitless. Necessarily I will therefore confine myself to a selected literature that is deemed most relevant in connection to historical materialism and the study of economic formations. I move from Karl Popper's criticism to historicism basically denying full scientific credentials to complex interpretations of history, and then consider some countercriticism by Edward Thompson defending the necessity of studying social inter-connections. In a subsequent section, I find John Elster's 'analytical Marxism' criticism to functionalism partially justified as long as it calls for the necessity of explaining how complex historical processes translate in granular individual choices. Edward Thompson's attempt at answering this question is discussed along with [START_REF] Ianulardo | Towards a unity of sense: a critical analysis of the concept of relation in methodological individualism and holism in economics[END_REF]. My idea is that agency is historically defined within material relations of production and in this it finds its intimate connection to structure. The conclusions underline some results. I shall defend a functionalist view of society while giving space to individual intentional action and aspirations, albeit informed by historical conditioning circumstances that affect agency. A historical reconstruction of the objective and subjective features of the economic formations under examination, rather than the aseptic and ahistorical study of individual choices unrelated to the social context, looks like the most promising way to go. Agency must be historically defined and studied.

Popper versus Thompson on how to study history

The list of Popper's allegations to historicism, of which one manifestation is traditional historical materialism, is well known and includes: the historicist claim to interpret history based on an 'intimate understanding of social phenomena' or 'essentialism' (Popper 1957, pp. 20, 28); the consequent claim of being capable of historical predictions based on identifiable historical laws (ibid, pp. 3, 36 and passim); holism, regarding a social group as 'more than the mere sum total of its members' where all 'social groups have their own traditions, their own institutions, their own rites' (ibid, pp. 17-18); organicism, 'the theory which interprets social groups by analogy with living organisms' (ibid p. 19), where 'society, like an organism, possesses a sort of memory of what we usually call its history' (ibid, p. 9). The historicist aspiration to provide strong interpretive accounts of historical events based on functional explanations is not disputed per se, but rather because it would lead to the formulation of too generic laws (ibid p. 26), expressed in purely qualitative terms (ibid p. 24) and therefore hardly falsifiable.: 'wholes (…) can never be the object of any activity, scientific or otherwise' (ibid, p. 77) while 'there is no motion of society in any sense similar or analogous to the motion of physical bodies' (ibid, p. 114).

To the historicist view Popper opposes piecemeal research that, to my eyes, represents the archetype of the current 'bright' and rampant marginalist economist: ideally dedicated to the study of circumscribed events describable by simple relationships on which to formulate clear and easily verifiable (or falsifiable) empirical hypotheses (ibid, p. 59). For her, historical research is 'characterized by its interest in actual, singular, or specific events, rather than in laws or generalizations ' (ibid, p. 143).

Indeed, there are elements of Popper's openness to a more connective work of the historian at least in the meticulous study of the 'situational logic in history', i.e., the objective circumstances that can explain certain historical decisions, going beyond history as the vicissitudes of great personalities (ibid, pp. 148-149). In this sense, Popper seems to transcend methodological individualism. The historian's work can also usefully reconstruct how social traditions are created, although the starting point remains methodological individualism: 'We need studies, based on methodological individualism, of the social institutions through which ideas may spread and captivate individuals, of the way in which new traditions may be created, and of the way in which traditions work and break down' (ibid, p. 149). The historian's work can even advance interpretive keys to history (economic, political, religious, etc.) that, however, would not be very falsifiable; therefore, the social scientist's point of view must clearly be expressed without claiming to advance general theories such as those possible in the natural sciences (ibid, pp. 150-152).

Before proceeding, I believe that one of Popper's objections to historicism and historical materialism can be removed, namely the claim of formulating prophecies about human destiny in scientific terms [4]. I believe that this is an unnecessary feature of holistic theories, at least of those with a materialist bias.

In them, for instance in Marxism, the prophetic aspect can well be removed without renouncing to a degree of organicism, and without therefore falling back into the renunciatory 'piecemeal engineering' to which Popper wants to relegate the work of social scientists. This is also the position of Edward Thompson (1978a, p. 20). He denounces that 'the nineteenth and twentieth centuries engendered authentic and sometimes monstrous "historicisms" (evolutionary, teleological, and essentialist notions of "history's" self-motivation)', acknowledging 'that this same historicism permeated some part of the Marxist tradition, in the notion of a programmed succession of historical "stages", motored towards a pre-determined end by class struggle', and concluding that: 'All this merited severe correction'. For Thompson this means surrender to 'the unknowability of any objective historical process', so that we 'must grope out way backwards in an empiricist dusk, making out the dim facts at our feet, piece-meal and one at a time ' (ibid, p. 22). In this way, Thompson notes, we 'will make sure that no facts escape from their discrete prison cells, enter into relationships, or hold mass meetings' (ibid, p. 34). True, Thompson acknowledges, the casuistic connection between historical facts is not subject to strong empirical testing but only to 'weak empiricism'. However, 'the inter-connections of social phenomena, causation within historical process -these seem to lie beyond any experimental test: hence a weak empiricism leaves us to stare uncomprehendingly at the world's most immediate manifestations, accepting them as what they are because that is what they seem to be' (ibid, p. 35). For Thompson while 'historians may take a decision to select' and 'write a history of discrete aspects of the whole (...), the real object remains unitary. The human past is not an aggregation of discrete histories but a unitary sum of human behaviour' (ibid. p. 40). Moreover, these processes are 'intelligible', in the sense that an 'understanding of the rationality (of causation, etc.) of historical process' or, in other words, 'an objective knowledge, disclosed in a dialogue with determinate evidence' is possible (ibid, p. 41).

Popper's criticism of historicism -letting aside the degenerative prophetic elements in some of its versions -mainly focuses upon the testability (falsifiability) of too complex historical interpretations. Agency and Elster on functionalism and methodological individualism Cesaratto (2023 b, c) examined some allegations of 'functionalism' made against historical materialism by exponents of (neoclassical) NIE. More specifically, [START_REF] Heijdra | Marxism, methodological individualism and the New Institutional Economics[END_REF] and [START_REF] Lowenberg | Neoclassical economics as a theory of politics and institutions[END_REF] maintained that the difference between Douglass North's NIE interpretation of history and Marx's own were not of substance but methodological: the first relying on methodological individualism and agency, the second on functionalism. A functional approach ultimately explains individual behaviour as part of social or institutional behaviours functional to the working of the whole system. Any system's component, in other words, is explained by the logic of the whole. This would, however, leave undemonstrated (or being indifferent to) how this functionality concretely takes place through individual micro-choices. This criticism has been anticipated by Popper who, as seen, associated the lack of testability of the holistic approaches to the lack of micro foundations. Particularly vehement and influential in this regard has been John Elster, one of the founders of 'analytical Marxism' [START_REF] Veneziani | Analytical Marxism[END_REF]. Elster (1982, p. 454) defines the Main Functional Paradigm as that in which 'the latent functions (if any) of an institution or behavior explain the presence of that institution or behavior'; while according to the Strong Functional Paradigm, 'all institutions or behavioral patterns have a function that explains their presence' (the distance between the two definitions is irrelevant for our present purposes).

Both would make the basic mistake 'to postulate a purpose without a purposive actor or, in grammatical terms, a predicate without a subject' (ibid, original emphasis ' (ibid, p. 457). These analyses rely at times on conspiracy explanations, other times on a cui prodest? (or cui bono?) way of arguing. In these explanations behaviours can be either intentional or unintentional (or in between). A particularly striking example is Michal [START_REF] Kalecki | Political aspects of full employment[END_REF] claim, inspired by Marx, about the functionality of unemployment to the capitalist social order, which may look specious at least if this is not supported by a detailed account of the underlaying decisional mechanism (intentional or unintentional). To prove the functionality of the 'industrial reserve army' to a well-functioning capitalism, Marx relied on the depressing effect of a lower normal profit rate on investment -when unemployment is too low and real wages higher. Lower investment would increase unemployment and restore profitability. Serrano (2004, p. 14) and Cesaratto (2015, pp. 167-169) argue that, however, a lower normal profit rate does not necessarily affect investment insofar as competition (out of fear of losing market shares) would lead capitalists to invest even at lower normal profit rates [7]. In fact, Kalecki excludes forms of collusion among capitalists on investment decisions (to reduce them, in this case) -his famous aphorism that '(…) capitalists do many things as a class but they certainly do not invest as a class' (Kalecki 1971, p. 152) well applies to this case. [START_REF] Kalecki | Political aspects of full employment[END_REF] suggests instead that the policy measures aimed at restoring normal profitability are taken by governments to ensure the capitalist social and distributive order. These measures consist of deliberate recessive policies that weaken labour's bargaining power. While these policies are functional to the status quo, the political mechanisms behind them are not, however, adumbrated.

In this regard, what Elster refutes is not functionality per se, which can well be legitimate; he would however claim that 'a mass of detailed evidence is required to make an intentional explanation credible' or that 'some mechanism must be provided if the [unintentional] explanation is to be taken seriously ' (ibid, pp. 461-462) [8]. As such, therefore, the criticism is not to functionalism per se, but to the incompleteness of its analytical usage, as I shall argue below. of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

The Journal of Philosophical Economics XVII (Annual issue) 2024 57

We can ask ourselves, though, whether functionalist cui prodest arguments -for instance, that liberal governments expectedly support investments' profitability -are so defective. Famously, the (supposed) champion of methodological individualism, Adam Smith (1776, pp. 68-69), in well-known passages openly talked of the tacit and sometimes open conspiratorial behaviour of capitalists meant to maintain the social order as a 'natural state of things which nobody ever hears of'. This power is difficult to unveil, but that one should be 'ignorant of the world' to deny it. This conspiracy power, often in collusion with politicians, is therefore difficult to uncover also for the historian, and a cui bono argument legitimately remains the only game in town.

Another founder of analytical Marxism, the late Gerald Cohen, engaged with Elster in a defence of functionalism in historical materialism. Cohen (1982a, p. 28) refers to functionalism as 'explanations in which, roughly speaking, consequences are used to explain causes', what he would call 'consequence law'.

In his opinion historical materialism is irremediably functionalist with particular regard to the superstructure which is functional to the preservation of its economic foundations. For instance, 'the legal system is explained by its function, which is to help sustain an economy of a particular kind ' (1982a, p. 31; 1982b, p. 487) 1982a, pp. 50-51, original italics; (2000 [1978]), p. 286). For instance, a plausible story on how wage discipline (A) may explain high unemployment (B), may be deemed necessary. Within historical materialism, Cohen admits, 'no one has given excellent answers ' (1982b, p. 488), conceding that 'if the question how the functional explanations of historical materialism explain (…) cannot even in principle be answered, then that would have lethal significance for historical materialism ' (1982a, p. 35). Persuasively, Cohen does not see a solution in game theory, as proposed by Elster, since it 'helps to explain the vicissitudes of the struggle, and the strategies pursued in it, but it cannot give a Marxist answer to the question why class wars (as opposed to battles) are settled one way rather than another ' (1982b, p. 489). In other words, game theory can explain moves and strategies (Cohen 1982a, p. 51;1982b, p. 490). This comparative method is indeed typical of social sciences like anthropology and archaeology. In fact, 'it would be a mistake to refrain from taking those explanatory steps which are open to us, just because we should prefer to go farther than our current knowledge permits' (Cohen 2000, p. 286). The situation would be somehow like Darwinism before genetics: functionality of natural behaviours explains their selection although the how was still unclear. Many, including Edward Thompson, have interpreted cultural history as (an additional) genetics of humans (I shall come back on this in the next section).

Thompson also suggests historical work on the making of collective subjectivities and choices (active as well as passive) as a complementary way out. Comparative historical work on how subjectivities coalesce under the given circumstances must complete functional analysis.

Thompson between agency and structure

In view of the above, historical work on individual and collective subjectivities emerging in their specific context, as a combination of comparative economic and institutional analyses (economic analysis being based on the surplus approach), may represent the way out from the functionalist trap. Elements in this direction are derived from a renowned exchange between Edward Thompson (1978a) and Perry [START_REF] Anderson | Arguments within English Marxism[END_REF].

As well known, Thompson (1978) is a book-long polemic against the undervaluing of historical analysis by Louis [START_REF] Althusser | For Marx[END_REF] and [START_REF] Althusser | Reading Capital[END_REF]. These authors would deem human agency irrelevant in view of the conditioning of the structural forces of historical materialism, the only (Thompson 1978a, p. 9). In other words, 'he evicts human agency from history, which then becomes a "process without a subject"' (ibid, p. 89), an expression we already found in Elster. Thompson looks at the idea of history as driven by forces independent of human action as a form of idealism (ibid, p. 4 and passim), one in which history is led by exogenous metaphysical forces [9].

In my opinion, Thompson's call for the study of how objective forces are translated in the historical process into human actions is not necessarily a slide into void subjectivity, but a necessary complement to the objective study of history. Otherwise, the risk is that a mechanistic approach to the dynamics of a mode of production, 'independent of the rationality and agency of the human actors', would soon prompt the question of 'whose is the divine will which programmed this automating structure, where is the ulterior "unconscious power"?' (ibid, p. 90, original italics).

Thus, what Thompson seems to be legitimately suggesting is the study of the translation of natural (material) forces through their historical unfolding in concrete human action (ibid, p. 85). The study of human agency in its historical evolving raises, of course, the question of 'intelligibility and intention' in human choices (ibid p. 84). For these "individual wills", however "particular" their "conditions of life", have been conditioned in class ways; and if the historical resultant is then seen as the outcome of a collision of contradictory class interests and forces, then we may see how human agency gives rise to an involuntary result -"the economic movement finally asserts itself as necessary" -and how we may say, at one and the same time, that "we make our own history" and "history makes itself" (ibid, p. 87, internal quotation from Engels' letter cited above).

In other words, it is the conflict among component vectors, representing classagency, that characterises history. The latter is thus generated by class agency and conflict, where individual class affiliation and interests -which may include the pursuit of technical change by the capitalist class and class conflict over its fruits -are deeply affected by objective socio-economic forces (see also Anderson 1980, p. 17) [10].

Strikingly, in the same vein, in his early manuscripts Sraffa talks of 'class mind' and refers to the importance of the 'historical side' along the analytical part. In studying the theories of prices and distribution, he argues, it 'will be thought that the important part is the analytical and constructive'. In this way, however, the 'significance of the historical side will be missed. And yet, this is the truly important, that which gives us a real insight into the mystery of human mind and understanding, into the deep unknown relations of individuals between themselves and between the individual and society (the social, or rather the class mind)' (quoted by Ginzburg 216,p. 47) [11]. As Ginzburg (ibid, p. 48) points out, although the adjective 'historical' (opposed to 'analytical') seems to refer to the historicity of economic theories, the quotation suggests a particular sensitivity by Sraffa to combining the economic and the anthropological sides of human relations, avoiding any form of 'economic determinism' (see also Le Donne 2022, p. 1120).

Less consensual I feel about Thompson's allegation of ahistoricism to Marx himself. By the end of the 1850s, the latter is said to have been caught in the trap of political economy by focusing on the abstract core of economic elements of capitalism whose historical dimension he had lost (Thompson 1978a, p. 59).

Thompson seems to miss here Marx's Herculean effort to refine the classical surplus approach particularly in addressing the unresolved problems of classical economics in the determination of the inverse relationship between the profit rate and the wage rate [START_REF] Garegnani | Value and distribution in the classical economists and Marx[END_REF][START_REF] Garegnani | On the labour theory of value in Marx and in the Marxist tradition[END_REF] [START_REF]For instance[END_REF]. Thompson has some merit, however, when he denounces that many pages of Capital (or Grundrisse) may convey the impression that 'capital' stands as an immanent force, 'the logic and forms of capital, to which men were subordinated' so that, in spite of 'Marx's Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

The Journal of Philosophical Economics XVII (Annual issue) 2024 61 imprecations against idealism', 'capital has become Idea, which unfolds itself in history' (Thompson 1978a, p. 60) [START_REF] Kolakowski | Thompson quotes here[END_REF].

Reasoning based on the 'logic of capital' may indeed be misleading. As an example, in his polemic against Friedrich List's economic nationalism, Marx (1845) overstated the transnational nature of capital [START_REF] Cesaratto | Harmonic and conflict views in international economic relations: a Sraffian view[END_REF]. The cosmopolitan 'logic of capital' led him to pay little attention (at this juncture) to the complexities of the history of capitalism -of national capitalisms in this case.

According to Thompson (1978a, pp. 53-54), more prudent than Marx had been the late Engels who presented economic laws as laws of tendency, imperfectly realised (in truth, Thompson concedes, elsewhere Marx also repeatedly emphasises the historical nature of economic laws). Thompson (1978a, p. 68) also criticises Althusser and his colleagues for seeking 'to thrust historical materialism back into the prison of the categories of Political Economy'. He acknowledges that Marx employed the concept of the circuit of capital to characterise the capitalist society, arguing however that 'historical materialism (…) must be concerned with other "circuits" also: the circuits of power, of the reproduction of ideology, etc., and these belong to a different logic and to other categories'. Moreover, he adds, 'historical analysis does not allow for static contemplation of "circuits" but is immersed in moments when all systems go and every circuit sparks across the other' (ibidem). As a result, historical materialism 'offers to study social process in its totality' (ibid, p. 70), where the emphasis is on the word 'process' that the English historian opposes to Althusser's (static) structure. In this way 'History' is 'put back upon her throne as the Queen of the humanities' (ibidem). So far so good. The dethroning of political economy, however, goes against the very centrality Thompson attributes to the concept of social class (and related class agency), unless the concept of class is defined on mere subjective and not on objective elements, leading the theory into indefiniteness. For Thompson political subjectivity is in fact a defining feature of the existence of social classes. In this sense Thompson argues for instance that: 'class struggle is the prior concept to class, class does not precede but arises out of struggle […] classes arise because men and women, in determinate productive relations, identify their antagonistic interests, and come to struggle, to think, and to value in class ways: thus the process of class formation is a process of self-making, although under conditions which are "given"' (ibid, p. 106-107). While an objective circumstance is present (the classes' antagonistic interests), this factor is for Thompson historically irrelevant as long as social class awareness does not arise. This is unacceptable and has been object of terse criticism by the late Oxford Marxist historian Geoffrey de Ste. Croix, who emphasised the objective nature of social classes with their existence being completely independent of class-consciousness (see Cesaratto 2023d, pp. 26-30).

In a similar vein, Anderson (1980, pp. 30-31) notes that in spite of the importance attributed to 'the productive relations into which men are born' and in which they mature the 'experience' later converted in 'class consciousness', the most celebrated of Thompson's works [START_REF] Thompson | The Making of the English Working Class[END_REF] 2013) almost lacks 'objectives coordinates' surrounding the process of (subjective) class formation. Anderson also notes that: 'Classes have frequently existed whose members did not "identify their antagonistic interests" in any process of common clarification or struggle ' (1980, p. 40, see also pp. 41-43). A similar stance in [START_REF] Cohen | Karl Marx's Theory of History. A Defence[END_REF] is quoted.

Anderson notes that elsewhere, indeed, Thompson would present a less unbalanced view of agency versus conditioning:

Where The Making of the English Working Class claimed that this making "owed as much to agency as to conditioning", "The Peculiarities of the English" [Thompson 1978d] warns its readers: "Let us look at history as history -men placed in actual contexts which they have not chosen, and confronted by indivertible forces, with an overwhelming immediacy of relations and duties and with only a scanty opportunity for inserting their own agency". (Anderson 1980, p. 48, original emphasis) Recourse to subjective factors like 'experience' and 'class consciousness', moreover, would be of little help to reconstruct the social texture or order that must find other, more objective foundations. For Marxism these would lie in the dominant mode of production since

The problem of social order is irresoluble so long as the answer to it is sought at the level of intention (…). It is, and must be, the dominant mode of production that confers fundamental unity on a social formation, allocating their objective positions to the classes within it, and distributing agents within each class. (…) class struggle itself is not a causal prius in the sustentation of order, for classes are constituted by modes of production, and not vice versa. (Anderson 1980, p. 55 bourgeois political economy' focusing only on the economic aspect of human activities' (Anderson 1980, p. 59).

On the contrary, for Anderson historical materialism found its 'full sense' only in the Grundrisse and in the 'Preface' of 1859 [START_REF] Marx | Preface' to A Contribution to the Critique of Political Economy[END_REF]):

It was this progressive theoretical discovery that finally made possible the full-scale exploration of a new historical object in Capital: the capitalist mode of production.

Marx's essential movement after 1848, in other words, was not "away" from history, but deeper into it. (…) Genetically and functionally, Marx's discovery of the concept of mode of production marks a decisive exit from the world of political economy; with it, he embarked on a new kind of history. (Anderson 1980, pp. 63-64, original emphasis) It is also surprising that on the one hand Thompson asserts the unity of socioeconomic analysis in historical materialism, while on the other hand he claims the autonomy, of 'the many activities and relations (of power, of consciousness, sexual, cultural, normative) which are not the concern of Political Economy' (Thompson 1978a, p. 59). In his book-long criticism of Thompson's Poverty of Theory, Perry Anderson (1980, p. 8) notes that 'Thompson does not attempt to expound or justify the specific set of categories that defines historical materialism', that is, he does not provide his own version of historical materialism, an absence of great momentum.

Drawing the threads of this section, the interest Thompson shows for the missing link 'between a mode of production and historical process' is stimulating. A link to the actual mechanism of change was missing, before Mendel, also in Darwinian theory:

For just as Darwin proposed and demonstrated an evolutionary process which proceeded by means of a hypothetical transmutation of the species -species which had hitherto been hypostasised as immutable and fixed -and yet remained wholly in the dark as to the actual genetic means of this transmission and transmutation -so, in an analogous way, historical materialism, as a hypothesis, was left unprovided with its own "genetics." If a correspondence could be proposed -and, in some part, demonstrated -between a mode of production and historical process, how, and in what ways, did this come about? (Thompson 1978a, p. 164) Thompson identifies the missing link in 'human experience'. But while genetics is an objective, material process (see next section), 'human experience' is a subjective outcome of something else, otherwise the term is an 'ambiguous void' (Anderson 1980, p. 80). For Thompson 'human experience' has contents of its own like morality and affectivity. 'Such a position -Anderson comments -has a respectable liberal pedigree, but it is not -plainly not -a Marxist one' [14]. Nonetheless, Anderson (1980, p. 83) points out, Thompson 'remains far more materialist as a historian' insisting that a 'materialist examination of values must situate itself, not by idealist propositions, but in the face of culture's material abode: the people's way of life, and, above all their productive and familial relationships' (Thompson 1978a, p 176). In this sense, I believe that despite some ambivalences, Edward Thompson's insistence on history must be welcomed, reconstructing human choices as the agency manifestation of deeper forces. His inconsistencies may be justified in view of the existential 'crucial ambivalence of our human presence in our own history, part-subjects, partobjects, the voluntary agents of our own involuntary determinations' (ibid, p. 88).

Contextualizing agency in archaeology

The discussion over agency and structure is lively in archaeology [START_REF] Bentley | Handbook of Archaeological Theories[END_REF]. Gardener (2007, p. 96) points out that whatever the degree of freedom humans have on their choices, agency is not an atomistic but a social action since 'what allows humans to fulfil their capacity for agency is their relationships (involvement) with other people and objects'. In other terms, 'Individuals only exist in relation to a physical and social world, and it is in the relationships that agency is manifested (…) agency is social and relational, and therefore situational' (ibid, pp.100, 103) [START_REF] Giddens | human agency within the scope of the reproduction of social structures[END_REF]. Notably, we saw Popper also using the term 'situational', while Marx (1857-8, p. 18) famously observed that '[t]he human being is in the most literal sense a ζῶον πολιτιχόν, [A political animal] not merely a gregarious animal, but an animal which can individuate itself only in the midst of society'. Bentley, Lipo, et al. (2007, p. 111) evolutionary archaeology (EA) would limit the extent of intentional choices given that the range of pursued intentions is itself part of the socially inherited context: human behavior is random with respect to natural selection through the evolutionary process of variation generation and then sorting of that variation (…). This does not mean that EA claims that people act randomly (which would be nonsense), but instead that intentions cannot themselves be an explanation for behavioral change because intentions are part of behavior, and therefore the subject of inheritance and natural selection of behavioral regularities. In this way, the intentions themselves are also potentially subject to evolution. (…) Human behavior is certainly nonrandom and imbibed with intention, but EAs argue that this is only an observation of the fact that our behavior is strongly inherited (culturally and genetically) using systems that include the inheritance of traits as well the inheritance of grammar (…). (ibid, pp. 115-116, emphasis added) Intentions are themselves part of the received cultural background, confirming Thompson's view of humans as 'the voluntary agents of our own involuntary determinations'.

This position puts some order in Engels's and Thompson's ambivalences about human agency, part subject and part object of history [17]. And, of course, the memory also goes to Marx's (1852, chapter 1, pp. n/a) famous sentence that 'Men make their own history, but they do not make it as they please; they do not make it under self-selected circumstances, but under circumstances existing already, given and transmitted from the past'.

Conversely, rational choice theories emphasize the ability of humans to make rational decisions in the given environment. Critics point out that, paradoxically, this is more plausible in simple societies, like the hunter-gatherers' communities, and much less in complex communities where individual behaviour is part of and conditioned by a much larger set of social mechanisms (Bentley, Lipo, et al. 2007, p. 119). In my opinion, criticism of the idea that subjects choose rationally goes too far. In fact, once the concept of rational choice is historicised (contextualised) it is perfectly permissible for individuals to make rational choices. This seems in line with the passage just quoted from Marx.

Rational choices are also often confused with socially beneficial choices. This is a legitimate liberal stance founded on the idea that rational self-interest and markets lead to optimal social results. This view is not shared by the supporters of the classical surplus approach and by Political Realism [18]. In their views, rational choices may well be socially conflictual, reflecting specific interests. In this sense I do not see any inconsistency between rational choices and conflictual view of society.

Within archaeology, the agency/structure dualism is central also in the 'processualism versus post-processualism' debate.

Processual or New Archaeology spread in Anglo-Saxon countries in the 1960s under the influence of a distinguished American archaeologist, the late Lewis Binford. It seems still currently prevailing in America despite post-Processualism, which sounds however more like a British or North European approach (Watson 2007, p. 33;Shanks 2007, pp. 133-134). New Archaeology explicitly searches for general laws, sharing materialism and functionalism with 'subsistence systems occupying center stage' (Watson 2007, p. 30;Trigger 2007, p. 407). Little attention is paid to individual agency and to the subjective points of view, concerns, or values of the studied populations (Trigger 2007, p. 401).

Human groups react rationally to stress produced by environmental change in a progressive process of adaptation (ibid, p. 395). Contiguity with Marxism's materialism has been noted (Trigger 1993, p. 186;Rosenswig 2012, p. 34;Saitta 1995, p. 557).

On the opposite front, interest in subjectivity became central in postprocessualism. Dismissing any grand theory, particularism is the dominant trait of post-processualism, while processual archaeology is considered 'too one-sided, too deterministic, too inflexible' (Shanks 2007, p. 135;Trigger 2007, p. 445). Postprocessualism challenges the old analytical conundrum of people being conditioned by pre-existing norms and structures that ensure social reproduction, emphasizing the chance of modifying these preconditions or anyway being proactive in their environment (Shanks 2007, p. 135):

instead of social systems and other social totalities, post-processual archaeology is interested in social subjects, thinking and plotting agents who work their way through society and history seeking goals, constantly sending out signals and signs, constantly interpreting the cultural signification around them. (ibid, p. 136) I feel deeply suspicious of these descriptions of human behaviour in which, ultimately, this is hanged to subjective, self-feeding beliefs and cultures. I feel for instance distant from 'culturalism' -a current of post-processual archaeology -which tries 'to capture "the native's point of view" as much as possible' (Viglietti of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

The Journal of Philosophical Economics XVII (Annual issue) 2024 67 2018, p. 226). However, I appreciate 'native conceptualization, experience, and cosmology' as an essential part of materialist interpretations -as long as beliefs are not taken at their face value and are somehow reconducted to some objective basis. In this sense I underline the complementarity between structural (or processual) analyses and the historical and anthropological reconstruction on how social groups and classes, ultimately the individuals, are the actual carriers of structural forces [19].

Post-processualism is said to be part of so-called post-modernism, a late 19 th century movement that has emphasised the subjective nature of knowledge, relativism, and agency, refusing 'modernist' grand theories and functionalism (e.g., Trigger 2007, pp. 446, 452). Post-modernism has also been influential in neo-Marxist theories in which an echo of the old diatribe between historicists and structuralists still resonates.

A recent Marxist debate

A recent paper by [START_REF] Knafo | Political Marxism and the rules of reproduction of capitalism: a historicist critique[END_REF] defends historicism and interpret Marxism as the study of human agency [20]. The paper rejects historical explanations based on the functionalist (or structuralist) 'logic of capital' with all privileges accorded to the production sphere, in favour of an agency-based 'historicist tradition… more directly inspired by E.P. Thompson' (ibid,p. 31). More specifically, referring to 'Marx's famous proposition', quoted above, 'that people make their history, even if not under the condition of their own making', Knafo and Teschke (ibid,p. 20) accuse historicism of leaving no space to people's choices and, reversing Marx's passage, they maintain that that the 'aim of the radical historicism (…) is to invert this classic framing of Marx's dictum (…) [in order] to reaffirm the fact that even if people do not determine the conditions they are placed in, it is still people who make history' (original emphasis).

These arguments sound however scarcely persuasive, reducing themselves to affirming that since it is people that make history (who can deny it?), therefore 'even if people do not determine the conditions they are placed in', people's action is the relevant issue, not the background circumstances. We are far away from the 'historical determined intentions' evoked above. As alluded in the introduction, Marx left us with two hypotheses about the 'laws of change' of modes of production referring, respectively, to the change in the 'forces of production' (the production technologies) and to class struggle (relations of production). The first hypothesis may look like a deus ex machina yet incapable to provide a systematic explanation of change in social formations, but further research is needed [23]. My limited historical knowledge does not allow me to judge if the second cause, class struggle, can provide such a systematic account either. As anticipated in the introduction, in my opinion, given the state of our knowledge, historical materialism is on a firmer base when concerned with the nature of a given mode of production by looking at institutions as regulating the historical forms of extraction and distribution of the social surplus [START_REF] Cesaratto | Schools of Athens: surplus approach, Marxism and institutions[END_REF]). Yet, historical materialism is much less well defined as a 'grand theory' of economic and institutional change (as traditional Marxism has perhaps believed). Reaction against technological determinism may sound therefore tolerable, without however arriving at the rejection of the association of institutions (formal and informal) with the material modes of exploitation and related evolution.

In a similar vein, Lafrance (2021, p.86) finds little merit in Knafo and Teschke's reliance on Edward Thompson to support their claim about the centrality of agency against structural analysis, and corroborates his judgment by quoting the English historian arguing that: 'I hope that nothing that I have written above has given rise to the notion that I suppose that the formation of class is independent of objective determinations, that class can be defined simply as a cultural formation, etc.' (Thompson 1978b, p. 149). Lafrance (2021, p. 87) then concludes that Thompson is far from rejecting the relation between human agency and the economic structure quoting him as also saying: 'What I am calling in question is not the centrality of the mode of production (and attendant relations of power and ownership) to any materialist understanding of history. I am calling in question […] the notion that it is possible to describe a mode of production [only] in "economic" terms' (quotations from Thompson 1978c, pp. 17-18).

I have added 'only' to the quotation to make it fully congruent with my point of view about the codetermination of historical forms of surplus production and distribution and the related institutional arrangements and behaviours (Cesaratto 2023a). Conversely, in approaches such as that of Knafo and Teschke all traces of the classical and Marx's surplus approach seem irretrievably lost. Saitta (1994, p. 204) properly notes in this regard that from a 'Marxist perspective (…) the most important problem with agency approaches in archaeology is their relative neglect of the surplus labour process in social life and the differential role of individuals and groups within it'.

Toward an encompassing theory of structure and agency? Individuals as social agents

In this journal, [START_REF] Ianulardo | Towards a unity of sense: a critical analysis of the concept of relation in methodological individualism and holism in economics[END_REF] recently set out to overcome the dichotomy between agency and structure. In synthesis, they argue that apart from a few extreme cases defined as 'methodological atomism' -for instance the proponents of the famous dictum that society does not exist (ibid, p. 200) -also the supporters of methodological individualism admit that individual choices cannot be independent of context (ibid, pp. 197, 215 and passim). For instance, sharp advocates of methodological individualism, such as Keith Arrow, admit that taking preferences as given in the analysis of choices (or technology in the case of production choices) without further investigation of the social background that generates them, is a limitation (ibid, pp. 208-209).

In holistic theories, conversely, 'individuals' beliefs, desires, and actions' are explained by the 'social framework ' (ibid, p. 201 and passim). Individuals are by definition social entities who do not live on their own initiative but, through the network of social relationships, in a way that is functional to the whole (ibid, p. 219). This considered, some authors would go so far as to argue that 'agency and structure are only two sides of the same coin' (ibid, p. 204), as in a system in which the whole depends on its parts. However, according to Ianulardo and Stella (ibid), this presumed Solomonic compromise leads to an analytical impasse: 'this is precisely what is problematic in the systemic view', namely that, 'if "agency" and "structure", or the components of a system and the system, are seen as two entities (or determinate identities), then this leads to the circle of presupposition'. In other words, 'it is true that individual preferences are determined by the social context, but so is the latter by the former. And this would make any explanation circular' (ibid). Therefore 'the systemic model does not represent an answer to the inadequacies of methodological individualism but amounts to nothing else than the vicious circle of presupposing' (ibid, p. 219), a chicken-and-egg puzzle.

The problem thus becomes how to overcome the partiality of the two opposing visions, holistic-systemic and individualistic, by recomposing the unity between agency and structure. However, the solution put forward by the two authors is unsatisfactory given its prescriptive or aspirational peculiarity. The authors talk of a 'sense of unity that is immanent in the relation' which 'is reflected on the individual side, in its drive towards others (…) as an internal push for the individual to go beyond himself and to create a unity', that is 'a communion that goes to constitute the society itself'. Symmetrically, society, 'cannot only be opposed to it, but must also be conceived as that communion, that is to say, that unity, in which the individual intends to achieve himself ' (ibid, p. 221).

The presence of a (sort of) communitarian teleologism or aspiration in their solution is openly admitted by Ianulardo and Stella (ibidem) who interpret 'the social process not so much in the light of the starting point, that is to say the difference that exists between the individual and society, as both methodological individualism and holism tend to do, but in the light of the end point, that is to say, the telos of the process itself and that is from the perspective of the unity of the individual and society'. They explicitly talk of a 'teleological perspective' (ibidem, original emphases).

This image of individuals striving to reunite in a social communion is reminiscent of old organicist theories that the authors had negatively valued (Marx 1945[START_REF] Marx | Theses on Feuerbach[END_REF]), 'is no abstraction inherent in each single individual. In its reality it is the ensemble of the social relations'. In Marx the intimate unity between the individual and the social structure was based in fact on the material reproduction of life and on their dialectic interaction [24].

In the German ideology Marx ([1845-46] 1968) argued in this direction:

[Human beings] begin to distinguish themselves from animals as soon as they begin to produce their means of subsistence, a step that is conditioned by their physical organisation. (…)

The fact is, therefore, that definite individuals who are productively active in a definite way enter into (…) definite social and political relations. (pp. N/A) It is the materiality of productive relations, the related production and distribution of social surplus, and the accompanying formal and informal institutions, that constitutes the inescapable link between structure and agency making the individual a social agent. Agency is shaped up by the structure reproduction patterns, changing them guided by socially and historically conditioned intentions. It is somewhat paradoxical to note that in a sense functionalism presupposes and explains human agency and ingenuity, both as a passive instrument of reproduction and as an active instrument of change [25].

A reference to the reproductive sphere, although in more edulcorated terms, is also present in Polanyi (see Cesaratto 2023a, p. 10).

The philosopher John [START_REF] Davis | The conception of the socially embedded individual[END_REF], often sympathetic to classical and Sraffian Economics, provides a solution somewhat opposite of that by Ianulardo and Stella to the question of 'how is it (…) that individuals are indeed agents when social structures are said to affect them?' (ibid, p. 94). While Ianulardo and Stella find the solution in the dissolvement of the individual in the community, Davis see it in the critical detachment of the individual from social conditioning in a process of self-awareness:

Social factors influence how individuals form self-concepts, but the idea that they are able to reflexively take themselves as subjects as objects of their thinking and activity, or objectify themselves as subjects, implies that individuals can detach themselves in some degree from the determining effects of social factors influencing them. This relative detachment allows us to suppose that individuals also influence social structures, just as social structures influence individuals, and enables us to then treat the idea of the individual being socially embedded as a coherent and meaningful conception. (ibidem, emphasis added)

It seems to me that Davis attributes an excessive capacity to economic agents to act in a somewhat critical manner in relation to the context in which they move. I would be more tempted to say that it is rather material interests that move choices, proactive or acquiescent of the status quo. Reflexivity, at least understood as the ability to question the status quo, would seem to be a privilege of the few, generally frowned upon by the ruling elite. Having said so, I am ready to admit that when individual critical thought merges with material social forces pushing for societal change, reflexivity can become a necessary intellectual and political component of that change. In this regard Ernesto Screpanti underlines the role of the subjectivity of 'concrete individuals who unite and organize themselves to change their living conditions' where 'science makes them agents who are more aware and renders their action more effective ' (2007, p. 65). This is a view inspired by the red thread connecting Machiavelli, Marx, and Gramsci, but that also evokes Edward Thompson's emphasis on collective action.

Conclusions

My thesis in this essay is that the functionalism that accompanies historical materialism is defensible when accompanied by the socio-historical analysis of the choices of agents, individual and collective. Such analysis is aimed at [26]. This is because it is in the fabric of social relations, ultimately related to the economic texture, that individuals as a social being, and their motivations and opportunities, are defined.

In this sense, it seems to me that we should pick up Edward Thompson's lesson, despite his many ambivalences over a slipping topic. Thompson captures the discomfort with mechanical formulations of historical materialism aimed at encapsulating in a simple formula the variety and complexity of given historical structures and their changes. To the best of current knowledge, it does not seem to me that such simplifications are possible, although archaeological research confirms the importance of material change. Possibly Marx himself falls in Capital into some form of Hegelianism in which the immanent force of capital governs everything, as Edward Thompson denounces. Yet, we must take inspiration from Marx, not always take him literally. It seems to me, nonetheless, that the core of historical materialism -the idea that the forms of exploitation, i.e. the extraction and distribution of surplus, are at the core of the socio-historical analysis co-determined with the institutions that regulate these forms -is sound and solid.

Methodological individualism, on the other hand, seems like a dead end. As is well known, Marx labelled as 'Robinsonades' the idea of '[p]roduction by an isolated individual outside society' arguing that it would be 'as much of an absurdity as is the development of language without individuals living together and talking to each other' (1857-8, p. 84). There is not such a thing as the individual agency, there is only socially defined agency. However, Marx forgave

Smith and Ricardo for sharing this absurdity as a reflection of the selfish individualism that characterises modern civil society. In fact, for Marx this is a liberating passage from more stifling past social orders as in 'this society of free competition, the individual appears detached from the natural bonds etc. which in earlier historical periods make him the accessory of a definite and limited human conglomerate' (ibid, p. 83). Genuine and altruistic individual freedom is in principle possible for Marx by the potential of modern science and technology and the consequent liberation from the world of paucity and human exploitation.

[18] In Political Sciences, liberals believe that rational choices lead to some social optimality. On the contrary, the emphasis of Political Realism is on conflict. This school took its inspiration from Thucydides, Machiavelli and Hobbes who identified forces such as the thirst for power and wealth, and the fear of losing them, as the dominant motives of human action. Machiavelli as in particular the inspirer of a modern and rational view of political action, separating, with ethical regret, politics, and morality.

[19] To be sure, I do not believe that any human subjective experience is necessarily linked to material economic factors and interests. The genetic background (e.g., Wisman 2023), the intimate and personal/family experiences that permeate our deep psychology, and the mysteries that surround our existence, are other determinants of the human experience, thought, and behaviour. As socially defined agents, respective social positions constitute the framework in which all determinants of the individual experience unfold. All components interact in yet not well understood ways. Once again, organicism is unavoidable!

Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

The Journal of Philosophical Economics XVII (Annual issue) 2024 77

[20] The journal Historical Materialism (vol. 29 (3), 2021) hosted a special issue devoted to discussing this paper.

[21] This paper is part of the symposium on [START_REF] Knafo | Political Marxism and the rules of reproduction of capitalism: a historicist critique[END_REF] mentioned in the previous footnote. I leave the other contributions to readers more initiated to the wordy intricacies of these Marxist debates.

[22] Lafrance (2021, p. 88) is less benevolent with Engels who late in his life, 'attempted to lessen this economic determinism by asserting the "relative independence" of superstructures from the "economic foundation". This, however, proved largely counterproductive, as it "inadvertently reinforced an economistic conception" of the economic base -"hiving off superstructures drained production itself of its social and cultural dimensions." ' (internal quotations from Sayer 1987)

[23] Paradoxically, recent mainstream research on the early emergence of inequality and related institutions has tried to generalize well-known archaeological findings and theories emphasising the role of material (say geographical) and technological circumstances as triggers of social change, for instance the cultivation of storable and taxable cereals [START_REF] Mayshar | The origin of the state: productivity or appropriability?[END_REF], the time-honoured 'hydraulic hypothesis' [START_REF] Allen | The economic origins of government[END_REF], or the adoption of the ox-drawn plough [START_REF] Bogaard | The farming-inequality nexus: new insights from ancient Western Eurasia[END_REF]. These studies unnecessarily embrace a neoclassical interpretive framework and openly reject the surplus approach, often in conflict with their sources of inspiration in archaeology that adopt it.

[24] Moreover, Marx's the final aspiration is not a merge of individual and structure, a sort of dilution of the individual in the community, but on the contrary individual freedom -once the reproduction of life is not anymore conditioned by scarcity and distributive injustice (see Screpanti 2007, p. 72 and passim). Ianulardo and Stella's 'sense of unity' is instead reminiscent of certain studies in socio-biology that focus upon 'ultrasocial' species of insects that practice division of labour and even agriculture and are socially stratified [START_REF] Wilson | Evolution "for the Good of the Group[END_REF][START_REF] Wilson | Human ultrasociality and the invisible hand: foundational developments in evolutionary science alter a foundational concept in economics[END_REF]. No doubt that in these societies there is not tension, not even dialectic, between individuals and the community, but perfect unity. Students of ultra sociality are however careful to apply these results to humans where culture, besides genes, has a larger role in determining behaviour and sense of social belonging (see above footnote [8]).

  Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84 Perry Anderson's criticism of Thompson's ambivalences. As said, the agency/structure conundrum is pervasive in social science. Some insights from archaeology are considered, particularly the idea, derived from evolutionary theory, of 'conditioned intentionality', in other words of agency constrained by the inherited socio-cultural context. The agency/structure debate has had a specific declination in Marxism during the mentioned long controversy between scholars more sensible to historicism, paying therefore wider attention to human agency in the historical vicissitudes, and structuralists, more sensible to theoretical and systemic explanations[3]. Recent Marxist authors have accentuated the emphasis on agency. I wonder whether anything Marxist is left in these 'post-modernist' approaches. I then discuss whether we might arrive at a unified view of agency and structure overcoming the chicken and egg dilemma envisaged by

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The Journal of Philosophical Economics XVII (Annual issue) 2024 55

	Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal
	of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84
	methodological individualism are involved insofar as piece meal methodology
	precisely regards the study of circumscribed situations in which testable
	hypothesis on agents' behaviour are feasible. Although sensitive to the argument
	of human agency, Thompson persuasively objected, with all due caution, that
	history should be treated as a whole and not in bits and pieces [6]. Not without
	effectiveness, agency and methodological individualism played a central role in
	later critiques to holistic approaches such as that by John Elster's 'analytical
	Marxism'.

56 The Journal of Philosophical Economics XVII (Annual issue) 2024

	Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal
	of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84
	individual level, the grand Marxist claims about macrostructures and long-term
	change are condemned to remain at the level of speculation' (ibid). Elster
	provides a provoking list of examples of functional analyses both in Marx and in
	Marxism in which 'various institutions of the capitalist era can be explained by
	their functions for capitalism
	). The wide adoption by Marxism of functionalism has devastating
	consequences since 'a firm knowledge about the mechanisms that operate at the

  , but not why the game exists at all, nor the nature of the conflict, or the asymmetric power of the conflicting players.Having excluded game theory, Cohen seems to suggest a historical way of solving the question of 'how A explains B' by finding 'instances', comparing historical situations in which similar institutions are generated functional to the working of the whole: 'For I think one can support the claim that [A] functionally explains [B] even when one cannot suggest what the mechanism is, if, instead, one can point to an appropriately varied range of instances in which, whenever [B] would be functional for [A], [B] appears'

Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

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during the game

  Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

The Journal of Philosophical Economics XVII (Annual issue) 2024 59 relevant ones: 'What Althusser overlooks is the dialogue between social being and social consciousness'

  Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

	point out that 'it is now understood that
	culture constitutes a second (in addition to genes) mechanism by which
	inheritance occurs.' Genetic selection is based on (i) a casual generation of
	genetic variations, (ii) an exogenous (environmental) selection mechanism, and

(iii) a vertical transmission among genetically related people. Humans intervene in the cultural transmission through 'intentional' actions while diffusion is also horizontal, among unrelated people

(ibid, pp.110-111)

[16]. Interestingly, The Journal of Philosophical Economics XVII (Annual issue) 2024 65

  Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

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68 The Journal of Philosophical Economics XVII (Annual issue) 2024

  Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84 Benevolently,Lafrance (2021, p. 88) [21] justifies Knafo and Teschke's uneasiness with traditional Marxism justified if referred to 'orthodox historical materialism' inspired by 'Marx's 1859 Preface to The Critique of Political Economy (…) elaborated by Engels (1878) in his Anti-Dühring (…) developed by leading Second International intellectuals, vulgarised by a Stalinised Third International, and revived by G.A. Cohen's Karl Marx's Theory of History'. This version of historical materialismasserts a determination of 'superstructural elements' such as law, state institutions and culture by an 'economic base'. It offers a technological-determinist reading of history as a pre-ordered sequence of modes of production, and understands the progression of forces of production as a transhistorical tendency being first facilitated and later impeded by a given set of relations of production, with class struggle playing a peripheral role as the conduit toward new relations of production, in line with this transhistorical tendency.(Lafrance 2021, p. 88) [22]

The Journal of Philosophical Economics XVII (Annual issue) 2024 69

  Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

The Journal of Philosophical Economics XVII (Annual issue) 2024 71 some

  Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84 pages before (ibid, p. 205) -where they include, alas, also Marx -precisely because they assumed imaginary collective entities hovering above individuals, like social memories, national spirits, or communitarian spiritualities.Nonetheless, there are two aspects that I find valuable in Ianulardo and Stella's 'solution': the search for a 'sense of unity' of the two terms of the dualism we are dealing with, and the idea of dialectics linking the two apparent opposites (on dialectics see also ibid, p. 211). Dialectics is again reminiscent of Hegelian idealism, and it is from this that Marx actually moved, but with a view to overcoming it in a materialist direction. The 'human essence', wrote Marx in thesis VI on Feuerbach

	What 'this emergent sense of unity that arises from each individual's self-
	transcendence' (ibid, p. 221) has to do with social and historical investigation of
	the concrete socio-economic formations is unclear and sounds like a step back
	towards idealism.

The Journal of Philosophical Economics XVII (Annual issue) 2024 73 reconstructing

  Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84 how structural relations, in particular the ways in which social surplus is extracted and distributed, translate into choices aimed at reproducing and possibly transforming the structure itself. Of course, what is described does not exhaust all human action, which also takes place on other levels, but it is a central aspect of it

The Journal of Philosophical Economics XVII (Annual issue) 2024However, this utopia is shattered by the genetic or social endurance of egoism and exploitative behaviours, as well as the difficulty of organising complex societies on new foundations. Free agency seems once again to be paying toll to objective forces.

The Journal of Philosophical Economics XVII (Annual issue) 2024

Acknowledgments

I thank the constructive comments of one of the referees, Giancarlo Ianulardo and Aldo Stella for useful remarks, Daniele Cesaratto for his explanations regarding the achievements of modern biology, and Giancarlo Bergamini for precious help in editing the paper.

Endnotes

[1] See Cesaratto and Di Bucchianico (2021 a, b); Cesaratto (2023a).

[2] An example of this criticism is Schumpeter's allegation to Adam Smith that in the Wealth of Nations everything is explained by division of labour leaving no space to individual agency. For instance, the Austrian economist argued that 'With A. Smith [division of labour] is practically the only factor in economic progress' being 'attributed to an inborn propensity to truck and its development to the gradual expansion of markets. …It thus appears and grows as an entirely impersonal force, and since it is the great motor of progress, this progress too is depersonalised' (Schumpeter 1954, pp. 187-188). It is well known that for the Scottish scholar talent was not innate but rather the result of division of labour, which might as well generate obtusity in the most repetitive jobs (cf. the classic [START_REF] Rosenberg | Adam Smith on the division of labour: two views or one?[END_REF][START_REF] Cesaratto | Notes on division of labour and economic growth: Smith, Schumpeter, Marshall[END_REF]. Certainly, Smith shared methodological individualism in a very prudent way (I shall return on Smith in the second section).

[3] Taccola (2022) provides a complete account of the lively debates among Italian Marxists on historicism over the last century. Thompson (1978a) represents a historicist criticism of structuralism a là Althusser.

[4] Popper's association of historicism/organicism and piecemeal research to, respectively, revolutionary or reformist political positions is not well founded. I believe that one can bend on the functionalist side and still believe in piecemeal social reforms.

[5] Thompson draws a parallel between Althusser's and Popper's criticisms of historicism, although carried out from almost opposite points of view: the privilege assigned to theory by the former, piecemeal engineering by the latter, both sacrificing history. Thompson's criticism of Althusser is evoked later in the text.

Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

The Journal of Philosophical Economics XVII (Annual issue) 2024 75

[6] For Thompson methodological individualism corresponds to explaining a soldier without defining an army or, out of metaphors, to describing individuals independently of their class background (ibid, p. 30). We shall see in the next section Thompson defending the role of agency in history rejecting, however, individual agency in favour of 'class agency'.

[7] In a Sraffian model of capital accumulation investment mainly depends on expected demand and not on the expected normal profit rate [START_REF] Cesaratto | Neo-Kaleckian and Sraffian controversies on the theory of accumulation[END_REF].

[8] Functional analysis would be admitted in biological sciences where behaviours (due to casual genetic variations) are selected, among other evolutionary forces, as a function of environmental or sexual fitness. 'Functional analysis, however, has no place in the social sciences, because there is no sociological analogy to the theory of natural selection' (Elster 1982, p. 463), although some attempts have been made, such as the 'meme theory' by Richard [START_REF] Dawkins | The Selfish Gene[END_REF]. In Darwinian theory lifetime variations, called phenotypic changes, do not indeed affect the genetic endowment and are not therefore transmitted. In biology, however, it is accepted that there is a 'cultural', nongenetic transmission, that spreads both horizontally and vertically to other individuals of the same or other generations, understood as the transmission of behavioural adaptations and learning processes pursued and acquired during lifetime. Such transmission does not only concern humans, where it likely plays a major role, but also other animals. The material manifestation of this kind of phonotypic transmission is likely in a modification in the neuronal circuits of the brain, which does not, however, spread genetically, but through social communication and material artifacts. Elster admits this kind of functional mechanisms 'in the case of natural-selection models of competition between firms' (ibid, p. 455). In this case a 'Lamarckian' rather than a Darwinian selection mechanism is often evoked in which variations during the agent's lifetime directly respond to environmental stimulus and are then transmitted to the offspring (say, to the next generation of managers).

[9] As seen, Thompson also condemns teleological historicism.

[10] Thompson's suggestion is not diminished by his inconsistencies as when he defines classes as a sum of individuals, as Anderson (1980, pp. 50-51) complains.

Cesaratto Sergio (2024), Agency, functionalism, and all that. A Sraffian view, The Journal of Philosophical Economics: Reflections on Economic and Social Issues, XVII (Annual issue), 48-84

Conflict of Interest Statement

The author declares that this research has no conflict of interest.


François-Xavier Boittin
email: francois-xavier.boittin@orange.fr

Kathia Beddek

Hélène Thery

Jérome Pateux

Guillaume Cosler

Diane Riccobono

Michel Drouet

Régis Bobe

F-X Boittin

The immunosuppressant drug cyclosporin A aggravates irradiation effects in endothelial cells

Keywords: Cyclosporine A, endothelial cells, ICAM-1, apoptosis, VE-Cadherin, actin cytoskeleton

Highlights

-CsA induces ICAM-1 overexpression through Toll-Like Receptor 4 (TLR4)-dependent NF-κb activation -CsA triggers apoptosis and rearrangement of the cytoskeleton and adherens junctions composed of VE-cadherin -CsA aggravates irradiation-induced ICAM-1 overexpression, apoptosis

Introduction

In the event of a nuclear accident, people may be exposed to high doses of irradiation, which can rapidly lead to a complete loss of white blood cells. Emergency treatments of this irradiation-induced haematopoietic syndrome include cytokines and growth factors, which may be efficient in the case of residual haematopoiesis, but bone marrow/haematopoietic stem cell transplantation may be necessary to allow recovery of haematopoiesis [START_REF] Drouet | Radiation victim management and the haematologist in the future: time to revisit therapeutic guidelines?[END_REF]. In case of allogeneic bone marrow/haematopoietic stem cell transplantation, immunosuppressive therapy is required to prevent graft-versus-host disease (GvHD) [START_REF] Choi | Current and emerging strategies for the prevention of graft-versushost disease[END_REF]. Among the available immunosuppressants, cyclosporin A (CsA, a calcineurin inhibitor) has been widely used in both experimental and clinical conditions to inhibit the release of pro-inflammatory cytokines, lymphocyte activation and proliferation, and development of GvHD [1;16]. In case of irradiation, CsA has also been used to prevent GvHD after haematopoietic stem cell transplantation [9;17]. However, in addition to its ability to prevent GvHD, CsA can induce endothelial dysfunction through multiple pathways including increased membrane expression of adhesion molecules and destabilisation of inter-endothelial junctions made of VE-Cadherin [4;13;14;21;22].

In addition to the haematopoietic syndrome, high dose irradiation is also known to induce endothelial dysfunction, including increased expression of adhesion molecules on the endothelial cell membrane (ICAM-1, V-CAM-1, P-and E-selectin), destabilisation of interendothelial junctions and endothelial cell apoptosis [11;15;19;20;25]. All of these effects of irradiation promote white blood cell migration into tissues, inflammation, development of oedema and can ultimately lead to hypoxia, alteration of tissues and organ failure [10;26].

As mentioned earlier, the deleterious vascular effects of CsA have been documented, but its effects on high-dose irradiated endothelial cells remain to be tested.

Here, we investigated the effect of CsA treatment on cultured human pulmonary microvascular endothelial cells (HPMECs) irradiated at high-dose. CsA alone triggered ICAM-1 overexpression through TLR4 and NF-κB activation, apoptosis and alterations of the actin cytoskeleton and VE-Cadherin adherens junctions in endothelial cells. We then show that CsA significantly exacerbates all the deleterious effects of irradiation on endothelial cells, including overexpression of membrane ICAM-1, apoptosis and rearrangement of the actin cytoskeleton and adherens junctions. Therefore, our results suggest that the use of an alternative immunosuppressant may be preferable after irradiation at high dose.

Materials and methods

Material

The immunosuppressive drug Cyclosporin A (CsA), the Toll-Like Receptor 4 (TLR4) inhibitors (M62812 and Tak242) and the NF-κB inhibitor BAY11-7085 were purchased from Tocris (Bristol, UK), while the TRPV4 agonist GSK1016790A was from Abcam (Cambridge, UK). The FITC-conjugated mouse anti-VE-Cadherin (CD144) antibody (clone 55-7H1, cat n° 580411) was from BD Pharmingen while Phalloidin 547 (FP-AZ0330) was from FluoProbes, Interchim, (Montluçon, France). DAPI Fluoromount-G TM mounting medium (cat n° 0100-20) was obtained from Southern biotech (Birmingham, AL 35209, USA). For flow cytometry analysis, all antibodies (BB515 mouse anti-human CD54 (ICAM-1, cat n° 564685), BUV737 mouse anti-human CD106 (VCAM-1, cat n° 565418), PE mouse anti-human CD62P (P-Selectin, cat n° 555524), APC mouse anti-human CD62E (E-Selectin, cat n° 551144)) and the FITC Annexin V/Propidium Iodide apoptosis detection kit were purchased from BD Biosciences.

Culture, irradiation and treatments of endothelial cells

Human pulmonary microvascular endothelial (HPMECs (Promocell, Switzerland)) were cultured in T25 flasks, 6-well plates (for cytometry measurements) or in 8-chamber Lab-Tek slides (for immunostainings) coated with attachment factor (Gibco). HPMECs were allowed to grow and reach confluence in endothelial cell growth medium MV2 (Promocell, Switzerland) containing endothelial cell growth medium supplement MV2 (Promocell, Switzerland) and Gentamicin/amphotericin (Gibco).

Human umbilical vein endothelial cells (HUVECs, Gibco) were also allowed to grow and reach confluence in T25 flasks or 6-well plates (for cytometry measurements) coated with attachment factor (Gibco). Medium 200 containing low serum growth supplement and Gentamicin/amphotericin (Gibco) was used to cultivate HUVECs. For both HPMECs and HUVECs, cells from passage 3 to 6 were used in experiments.

Confluent HPMECs were irradiated at 15 Gy (dose-rate of 0,68 Gy/min) using an X-irradiator (SARRP (Xstrahl, UK). High accuracy dosimetry was performed using small pieces of Gafchromic paper, as previously described [START_REF] Dos | Dosimetry for Cell Irradiation using Orthovoltage (40-300 kV) X-Ray Facilities[END_REF].

In some experiments, HPMECs were treated with CsA 24 h after being irradiated, as indicated in the figures. In experiments from Fig. 1 and 2C, HPMECs were treated with CsA for 24 h before measurements, while TLR4 or NF-κB inhibitors were added 10 min before treatment with CsA.

Immunostaining

HPMECs cultured in 8-chamber Lab-Tek slides were washed with DPBS, fixed with paraformaldehyde 2 % for 15 min and permeabilized with Triton X-100 (0.2 %) for 3 min at room temperature. Before being stained, HPMECs were incubated with 5 % bovine serum albumin in DPBS for 1 h at room temperature, in order to prevent non-specific labelling.

HPMECs were then stained with FITC-conjugated mouse anti-CD144 (VE-Cadherin) antibody (1:5) and Phalloidin 547 (1:250) for 45 min at room temperature [START_REF] Beddek | TRPV4 channel activation induces the transition of venous and arterial endothelial cells toward a proinflammatory phenotype[END_REF]. After extensive washing, coverslips were mounted on glass slides using DAPI Fluoromount-G TM . An OLYMPUS IX2-SLP microscope equipped with a Hamamatsu Orca-Flash4.0 V2 camera and NIS Elements Nikon software (version 4.51.00) was used to acquire images. All acquisition parameters were kept the same for all conditions in each experiment (laser power, exposition time).

Apoptosis assay

As described before, a FITC Annexin V/Propidium Iodide apoptosis detection kit (BD Biosciences) was used to measure apoptosis and necrosis in HPMECs [START_REF] Beddek | TRPV4 channel activation induces the transition of venous and arterial endothelial cells toward a proinflammatory phenotype[END_REF]. Cells cultured in 6well plates were detached and washed twice with cold PBS. HPMECs were then resuspended in binding buffer (100 μl) and incubated with 5 μl FITC Annexin V and 5 μl Propidium Iodide (PI) for 15 min at 20 °C in the dark. After further addition of binding buffer, apoptosis of HPMECs was rapidly analysed by flow cytometry using a Becton Dickinson LSR II cytometer. FlowJo software was used to perform analysis, enabling to calculate the % of apoptotic cells (PI+, FITC Annexin V+).

Measurements of endothelial cell surface expression of adhesion molecules

Membrane expression of adhesion molecules (ICAM-1, VCAM-1, P-selectin and E-selectin).

was measured by flow cytometry for HPMECs and HUVECs, as described previously [START_REF] Beddek | TRPV4 channel activation induces the transition of venous and arterial endothelial cells toward a proinflammatory phenotype[END_REF].

Briefly, cells cultured in 6-well plates, were detached, washed and fixed with PBS containing 1 % paraformaldehyde. Cells were then washed and stained (30 min) with a four colours antibody panel composed of BB515 mouse anti-human CD54 (ICAM-1), BUV737 mouse anti-human CD106 (VCAM-1), PE mouse anti human CD62P (P-selectin) and APC mouse anti-human CD62E (E-selectin). After extensive washing with PBS, cell staining was analysed by flow cytometry using a Becton Dickinson LSR II cytometer. An anti-Mouse Ig, κ/Negative control compensation particles set (BD Biosciences) was used to set compensations in each experiment. FlowJo software was used to analyse all data, using Median Fluorescence Intensity (MFI) values to compare cell surface expression of ICAM-1, P-selectin, E-selectin and VCAM-1 in control and after cell irradiation/treatment.

Statistical analysis

Data are expressed as means +/-SEM. Statistical significance was evaluated with ANOVA tests, using GraphPad Prism software (San Diego, CA).

Results

Cyclosporin A increases the membrane expression level of ICAM-1 in human pulmonary microvascular endothelial cells.

Confluent HPMECs were incubated for 24 h with CsA (1, 10 and 30 µM). After 24 h of incubation, cells were detached, fixed and membrane expression levels of adhesion molecules (ICAM-1, VCAM-1, E-selectin, P-selectin) were measured by flow cytometry. The membrane expression level of ICAM-1 was significantly increased after 24 h of CsA exposure at concentrations ≥ 10 µM, as indicated by significant increases in ICAM-1 MFI (Fig. 1A). In contrast, the membrane expression levels of other adhesion molecules (VCAM-1, P-selectin and E-selectin) remained unchanged after 24 h of incubation with CsA, even at the highest concentration tested (Fig. 1A).

ICAM-1 gene expression is mainly controlled by the transcription factor NF-κB [START_REF] Xue | NF-kappaB regulates thrombin-induced ICAM-1 gene expression in cooperation with NFAT by binding to the intronic NF-kappaB site in the ICAM-1 gene[END_REF]. To investigate whether the CsA-induced increase in ICAM-1 membrane expression is indeed related to NF-κB activation, we tested the effect of BAY11-7085, a potent inhibitor of NF-κB activity [START_REF] Hu | An IkappaBalpha inhibitor causes leukemia cell death through a p38 MAP kinase-dependent, NF-kappaB-independent mechanism[END_REF]. As shown in Fig. 1B, pre-incubation of HPMECs with BAY11-7085 (10 µM) abolished the effect of CsA on ICAM-1 membrane expression, indicating that it relies on NF-κB activation. Moreover, pre-treatment of HPMECs with the potent Toll-Like Receptor 4 (TLR4) inhibitors M62812 or Tak242 significantly reduced CsA-induced ICAM-1 overexpression, suggesting that the CsA-induced NF-κB activation may be achieved through TLR4 activation by CsA (Fig. 1B) [18;23].

Cyclosporin A aggravates irradiation-induced overexpression of membrane ICAM-1 in pulmonary microvascular endothelial cells

HPMECs were irradiated at high dose (15 Gy, X-irradiation) and CsA was added to the cell culture medium 24 h after irradiation. Measurements were then performed 48 h after irradiation. The results in the Fig. 2A indicate that irradiation induced overexpression of ICAM-1, and also that the addition of CsA (at concentrations ≥ 10 µM) to irradiated HPMECs triggered a significant increase in ICAM-1 expression compared to cells that had only been irradiated (Fig. 2A). In contrast, the plasma membrane expression of the other adhesion molecules investigated (E-and P-selectin, VCAM-1) was not significantly affected by irradiation or CsA (Fig. 2A). These experiments therefore suggest that the enhanced increase in ICAM-1 membrane expression observed in irradiated HPMECs exposed to CsA relies on the additive effects of CsA and irradiation.

Cyclosporin A increases the membrane ICAM-1 overexpression induced by cytosolic

Ca 2+ increases related to Ca 2+ entry through TRP channels in macrovascular endothelial cells As shown for HPMECs, only the membrane expression level of ICAM-1 was significantly increased in macrovascular endothelial cells (HUVECs) after 24 h exposure to CSA at concentrations ≥ 10 µM (Fig. 2B). We have recently shown that Ca 2+ entry through Transient Receptor Vanilloid 4 channels (TRPV4) significantly increased the membrane expression level of ICAM-1 in macrovascular endothelial cells [START_REF] Beddek | TRPV4 channel activation induces the transition of venous and arterial endothelial cells toward a proinflammatory phenotype[END_REF]. Here, preincubation of HUVECs with 30 nM GSK1016790A (a potent TRPV4 agonist [START_REF] Beddek | TRPV4 channel activation induces the transition of venous and arterial endothelial cells toward a proinflammatory phenotype[END_REF]) induced an ICAM-1 overexpression that was significantly increased in the presence of CSA at concentrations ≥ 10 µM (Fig. 2B).

These results indicate that an additive effect of CsA and the TRP channel agonist (GSK1016790A) is involved in ICAM-1 overexpression.

Cyclosporin A induces apoptosis in microvascular endothelial cells

HPMECs were incubated with CsA alone (1, 10 and 30 µM) and apoptosis was evaluated 24 h after CsA addition, using a FITC Annexin V/Propidium Iodide apoptosis detection kit. Even at the lowest concentration tested (1 µM), CsA triggered significant apoptosis in HPMEC monolayers (Fig. 3A andB). In contrast to what was observed for ICAM-1 overexpression, CsA-induced apoptosis was not inhibited by blocking TLR4 receptors with M62812 or Tak242 (Fig. 3C) [18;23]. Apoptosis was even significantly higher with M62812 treatment, suggesting that TLR4 blockade may promote apoptosis in HPMECs (Fig. 3C).

Cyclosporin A aggravates irradiation-induced apoptosis in microvascular endothelial cells

High-dose irradiation (15 Gy) triggered significant apoptosis of HPMECs when measured 72 h after irradiation, as indicated by the significant increases in the apoptotic cell fraction (Fig 3D). When a low CsA concentration (1 µM) was added 24 h after irradiation, we observed a significant increase of the apoptotic fraction of HPMECs (Fig. 3D). Therefore, even low concentrations of CsA aggravate irradiation-induced apoptosis of HPMECs.

Effects of Cyclosporin A and irradiation on the cytoskeleton and adherens junctions in

HPMECs

To investigate the effects of CsA and irradiation on the actin cytoskeleton and adherens junction in HPMECs, cells were stained with Phalloidin and anti-VE-Cadherin antibody.

While actin appeared to be predominantly localised near the plasma membrane in control cells, high concentrations of CsA (10 and 30 µM) induced an obvious rearrangement of the cytoskeleton, with a marked increase of peripheral intracellular F-Actin associated with the formation of Phalloidin-stained F-Actin stress fibres (Fig. 4). In addition, VE-Cadherin staining at plasma membrane appeared more winding after exposure of HPMECs to high concentrations of CsA (30 µM), indicating a rearrangement of plasma membrane VE-Cadherin (Fig. 4).

High-dose irradiation (15 Gy) also triggered a rearrangement of the actin cytoskeleton with the formation of stress fibres, as high intensity F-Actin staining was more frequently observed near the plasma membrane and in the cell cytosol. However, in contrast to CsA treatment, no obvious alteration of VE-Cadherin staining was observed after irradiation with this protocol.

In HMPECs irradiated at 15 Gy and exposed to CsA, the formation of actin stress fibres and a VE-Cadherin rearrangement were observed, but these effects were enhanced when compared to cells exposed to CsA alone (Fig. 4). Indeed, even for the lowest CsA concentration tested (1 µM), the formation of actin stress fibres was increased in irradiated cells. Moreover, extensive intercellular gaps were highly visible in HMPECs irradiated at 15 Gy and exposed to CsA (10 and 30 µM), indicating that many cells in the endothelial monolayer were no longer joined (arrows in Fig. 4). Overall, these results indicate that the effects of CsA on the cytoskeleton and adherens junctions are additional to those of irradiation and also that CsA significantly aggravates the effect of irradiation on endothelial monolayers.

Discussion

Here, we investigated the effect of CsA, a widely used immunosuppressant, on human microvascular pulmonary endothelial cells exposed to high-dose X-ray.

We first show that exposure to CsA alone increased the membrane expression of ICAM-1 in both microvascular (HPMECs) and macrovascular (HUVECs) endothelial cells [2;4;21]. This effect of CsA was significantly reduced by potent inhibitors of both NF-κB and TLR4 receptors, suggesting that the stimulation of ICAM-1 expression by CsA includes TLR4dependent activation of NF-κB in HPMECs, consistent with a recent study in murine endothelial cells [START_REF] Rodrigues-Diez | Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling[END_REF].

High-dose irradiation of HPMECs (15 Gy) also triggered increased membrane expression of ICAM-1 and post-irradiation treatment of irradiated HPMECs with CsA significantly increased the stimulatory effect of high-dose X-irradiation on ICAM-1 expression. In fact, the effects of CsA and irradiation appeared to be additive with respect to ICAM-1 membrane expression. This additive effect of CsA was also observed when ICAM-1 expression was induced by a completely different mechanism (Ca 2+ entry through TRPV4 channels) in another endothelial cell type (HUVECs), suggesting that it may occur regardless of the pathway triggering ICAM-1 overexpression [START_REF] Beddek | TRPV4 channel activation induces the transition of venous and arterial endothelial cells toward a proinflammatory phenotype[END_REF]. Furthermore, both low concentrations of CsA and high-dose irradiation triggered significant apoptosis in HPMEC cultures and, as was the case for ICAM-1 expression, the pro-apoptotic effect of CsA adds to that of irradiation regarding apoptosis of HPMECs. Finally, CsA significantly altered the actin cytoskeleton and adherens junctions, as evidenced by the formation of actin stress fibres and the rearrangement of VE-cadherin adherens junctions.

Rearrangement of the actin cytoskeleton was also observed upon irradiation, with the formation of actin stress fibres. The effects of CsA on the cytoskeleton, adherens junctions and monolayer integrity were enhanced in irradiated HPMECs, indicating that CsA also significantly worsens the effect of irradiation on endothelial monolayers.

Overall, our results indicate that CsA alone induces ICAM-1 overexpression, apoptosis, actin stress fibre formation and adherens junction rearrangement, but more importantly that most of these deleterious effects are additional to those of irradiation and observed for CsA concentrations in the micromolar range, which corresponds to the CsA peak blood concentration in patients treated with this immunosuppressant [START_REF] Gerull | Cyclosporine levels and rate of graft rejection following non-myeloablative conditioning for allogeneic hematopoietic SCT[END_REF].

Upon irradiation, leucocyte migration through the endothelium is facilitated by overexpression of ICAM-1, endothelial cell apoptosis and deregulation/rearrangement of the adherens junction, which ultimately promotes the development of excessive inflammation [10;11;15;19;20;25;26]. As CsA enhances all these effects, this suggests that post-irradiation treatment with CsA may significantly worsen the pro-inflammatory effects of irradiation, leading to increased tissue alteration and organ damages. In line with this hypothesis, it has recently been demonstrated in NOD scid gamma mice that CsA treatment combined with irradiation is hepatotoxic and even lethal [START_REF] Walcher | Effect of combined sublethal X-ray irradiation and cyclosporine A treatment in NOD scid gamma (NSG) mice[END_REF]. Therefore, the additive deleterious effects of CsA on irradiated endothelial cells that we describe in the present work may partly explain the in vivo observations of these authors.

Conclusion

CsA has been widely used to prevent GvHD after transplantation, including bone marrow/haematopoietic stem cell transplantation required to restore haematopoiesis after to high-dose radiation exposure [1;9;16;17]. Therefore, the results presented here suggest that in case of bone marrow/haematopoietic stem cell graft/transplantation after accidental high-dose irradiation, the use of CsA as an immunosuppressant may aggravate the deleterious effect of irradiation on the endothelium, which could ultimately worsen inflammation, oedema and long-term tissue alterations caused by high-dose irradiation. Alternative immunosuppressant treatments may then be considered after bone marrow/haematopoietic stem cell graft/transplantation in case of irradiation.

Aknowledgments Grants

This work was supported by a grant from DGA (Direction Générale de l'Armement, grant n° PDH2-NRBC4-NR4301).

Disclosures

The authors declare no conflicts of interest.

Figure legends

Fig. 1 .

 1 Fig. 1. Effect of CsA on the surface expression of ICAM-1, VCAM-1, E-selectin and P-

Fig. 2 .

 2 Fig. 2. Effect of CsA treatment on irradiation-or Ca 2+ entry-induced ICAM-1

Fig. 3 .

 3 Fig. 3. Effect of CsA and high-dose irradiation (15 Gy) on apoptosis of HPMECs. A:

Fig. 4 .

 4 Fig. 4. Effect of CsA and high-dose irradiation (15 Gy) on the actin cytoskeleton and