the main advantages of using the zebrafish to model inflammation and inflammasomes, describing 48 how this model has highlighted the importance of inflammasomes in hematopoiesis. Indeed, this 49 model may help explain the hematopoietic lineage bias that has been associated with chronic inflam-50 mation in humans, revealing novel candidate therapeutic targets for future investigation in some of 51 these diseases. (See Box 1.) Q8 52 Inflammasomes 53 Inflammasomes act as sensors of the innate immune system in vertebrates, and promote in-54 flammation in response to various stimuli, including infection, tissue damage, or metabolic dys-55 regulation. They are multiprotein complexes formed by a receptor, the adaptor protein 56 apoptosis-associated speck-like protein containing a CARD (ASC), and an effector that 57 interacts through homotypic interactions [18]. Recently, the guanylate-binding protein (GBP) 58 family was found to also form a part of these multiprotein complexes in humans, mice, and 59 zebrafish [19-22]. Inflammasomes act by activating inflammatory caspases, namely caspase 60 1 (CASP1) (canonical inflammasomes), and CASP4, CASP5 (human), and Casp11 (mouse) 61 (noncanonical inflammasomes) [18]. 62 Inflammasome sensors are grouped, depending on their structure, into nucleotide-binding do-63 main (NOD)-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), 64 or pyrin [18]. When a specific stimulus is detected, the sensor interacts with and promotes the 65 oligomerization of ASC, which forms specks and is able to recruit and activate inflammatory Trends Trends in in Immunology Immunology b1:10 specks are able to propagate inflammation in mouse models of CAPS and are found in the serum of patients with CAPS, b1:11 but not with FMF [60,61] . Therefore, macrophage-derived ASC specks may be taken up by HSPCs, activating b1:12 their inflammasome and further enhancing myelopoiesis at the expense of erythropoiesis, which might explain the iron-b1:13 resistance anemia-associated with CAPS (see Clinician's Corner and Outstanding Questions) (Figure 2).

Dear author,

Please note that changes made in the online proofing system will be added to the article before publication but are not reflected in this PDF.

We also ask that this file not be used for submitting corrections. Lola Rodríguez-Ruiz, 1 Juan M. Lozano-Gil, 1 Christophe Lachaud, 2 Pablo Mesa del Castillo, 3 María L. Cayuela, 3 Diana García-Moreno, 1, * Ana B. Pérez-Oliva, 1, * and Victoriano Mulero 1, * Hematopoiesis is a complex process through which immature bone marrow precursor cells mature into all types of blood cells. Although the association of hematopoietic lineage bias (including anemia and neutrophilia) with chronic inflammatory diseases has long been appreciated, the causes involved are obscure. Recently, cytosolic multiprotein inflammasome complexes were shown to activate inflammatory and immune responses, and directly regulate hematopoiesis in zebrafish models; this was deemed to occur via cleavage and inactivation of the master erythroid transcription factor GATA1. Herein summarized are the zebrafish models that are currently available to study this unappreciated role of inflammasome-mediated regulation of hematopoiesis. Novel putative therapeutic strategies, for the treatment of hematopoietic alterations associated with chronic inflammatory diseases in humans, are also proposed.

Hematopoietic Lineage Bias in Chronic Inflammation

Hematopoiesis is the complete process of blood cell formation occurring during embryonic development and adulthood. In vertebrates, this process involves two phases. First, during embryonic development, the primitive hematopoietic wave (see Glossary) is transitory, and the erythroid and myeloid progenitor cells lack pluripotency [START_REF] Palis | Yolk-sac hematopoiesis: the first blood cells of mouse and man[END_REF]. In the second phase, the definitive hematopoietic wave [START_REF] Mcgrath | A transient definitive erythroid lineage with unique regulation of the β-globin locus in the mammalian embryo[END_REF][START_REF] Bertrand | Definitive hematopoiesis initiates through a committed erythromyeloid progenitor in the zebrafish embryo[END_REF], which occurs at later stages of development, hematopoietic stem cells (HSCs) emerge and give rise to all types of blood cells in adult organisms [4]. HSC maturation involves the differentiation of lymphoid [T, B, and natural killer (NK) cells], myeloid (granulocytes and macrophages), and erythroid (megakaryocytes, erythrocytes) cell lineages [START_REF] Weissman | Translating stem and progenitor cell biology to the clinic: barriers and opportunities[END_REF][START_REF] Kondo | Biology of hematopoietic stem cells and progenitors: implications for clinical application[END_REF][START_REF] Kondo | Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors[END_REF]. Several signaling pathways orchestrate this complex process, by means of different transcription factors regulating the maturation, proliferation, and differentiation of hematopoietic cells. The transcription factors GATA1 and SPI1 (also known as PU.1), are essential and present a cross-inhibitory relationship [START_REF] Zhang | PU.1 inhibits GATA-1 function and 344 erythroid differentiation by blocking GATA-1 DNA binding[END_REF][START_REF] Rekhtman | Direct interaction of hematopoietic 347 transcription factors PU.1 and GATA-1: functional antagonism 348 in erythroid cells[END_REF] (Figure 1): GATA1 regulates erythroid differentiation [START_REF] Cantor | Transcriptional regulation of 350 erythropoiesis: an affair involving multiple partners[END_REF], and SPI1 regulates myeloid differentiation [START_REF] Scott | Requirement of transcription factor PU.1 353 in the development of multiple hematopoietic lineages[END_REF]. However, there are many controversies regarding the factors that may be responsible for terminal erythroid and myeloid differentiation, and the involvement of the HSC niche Q7 in these processes [START_REF] Wattrus | Stem cell safe harbor: the hema-356 topoietic stem cell niche in zebrafish[END_REF], given that many unknown pathways seem to play a role in this complex biological process [START_REF] Cantor | Transcriptional regulation of 350 erythropoiesis: an affair involving multiple partners[END_REF][START_REF] Hoppe | Early myeloid lineage choice is not initiated 358 by random PU.1 to GATA1 protein ratios[END_REF]. For example, while GATA1 in hematopoietic precursors directs commitment to the erythroid-megakaryocyte lineage [START_REF] Iwasaki | GATA-1 converts lymphoid and 360 myelomonocytic progenitors into the megakaryocyte[END_REF], the overexpression of GATA1 in erythroid cells inhibits their terminal differentiation in mouse [15]. In addition, GATA1 expression and activity increase in the initial stage of erythroid differentiation, but they both decrease in later stages to allow terminal erythroid differentiation in mouse and human [START_REF] Ferreira | GATA1 function, a paradigm for transcrip-366 tion factors in hematopoiesis[END_REF]. All these complex pathways might have important clinical implications, since hematopoietic lineage bias, mainly neutrophilia and anemia, are associated with an increased incidence of disease, at least for 30 pathologies with prominent inflammatory components, including infection, rheumatoid arthritis, atherosclerosis, inflammatory bowel diseases, kidney and pulmonary diseases, autoimmune conditions, neurodegenerative diseases, and cancer [START_REF] Elias | Molecular mechanisms underlying line-368 age bias in aging hematopoiesis[END_REF]. In this review, the general structure and function of mammalian inflammasomes, and the specificities of macrophage and neutrophil inflammasomes (which are the best characterized), are summarized. Then follows a discussion on

Highlights

The activation of the Nlrp1a inflammasome in mouse hematopoietic stem and progenitor cells (HSPCs) triggers their pyroptotic death and prolonged leukopenia upon chemotherapy or viral infection.

The NLRP3 inflammasome drives HSPC clonal expansion and pyroptosis in myelodysplastic syndrome patients.

Emerging evidence from zebrafish models suggests that the canonical inflammasome autonomously regulates the erythroid-myeloid cell fate decision of HSPCs, and terminal erythroid differentiation through the cleavage of Gata1. This mechanism appears to be evolutionarily conserved since pharmacological inhibition of caspase 1 (Casp1) in mouse hematopoietic stem cells (HSCs) results in a rapid increase in Gata1 protein, leading to erythroid differentiation.

Pharmacological inhibition of the canonical inflammasome rescues zebrafish disease models of neutrophilic inflammation, anemia associated with chronic diseases, and Diamond-Blackfan anemia.

U N C O R R E C T E D P R O O F Figure 1. Regulation Q1
of HSPC Lineage Decision Choice by the Canonical Inflammasome in Zebrafish and Mouse. Activation of the inflammasome in HSPCs results in the cleavage and inactivation of GATA1, promoting increased amounts of SPI1 that promotes myeloid differentiation. Conversely, inhibition of the inflammasome in HSPCs results in an increased GATA1 amount that promotes erythroid differentiation [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF]. Abbreviation: CASP1, caspase 1; HSPCs, hematopoietic stem and progenitor cells. driven by germ-line mutations in genes encoding inflammasome components. FMF is the most common monogenic b1:5 autoinflammatory disease worldwide, affecting an estimated 150 000 patients [START_REF] Portincasa | Colchicine, biologic agents and more for the treatment of familial Mediterranean fever. The old, the new, and the rare[END_REF]. More than 60% of FMF patients b1:6 develop anemia that is associated with iron status rather than inflammation, assayed as plasma IL-6 concentrations b1:7 [START_REF] Celkan | The anemia of familial Mediterranean fever disease[END_REF]. Similarly, iron-resistant hypochromic anemia has also been associated with CAPS [START_REF] Prieur | A chronic, infantile, neurological, cutaneous, and articular (CINCA) syndrome. A specific entity analysed in 30 patients[END_REF]. It is tempting to speculate that b1:8 overactivation of the inflammasome in HSPCs could directly promote anemia by enforcing erythropoiesis, explaining the b1:9 usual iron-refractory nature Q3 of these diseases, but this remains to be robustly investigated. Furthermore, released Asc

U N C O R R E C T E D P R O O F caspases.
For a long time, CASP1 autoproteolysis was deemed to be triggered by the proximity of its active subunits p20 and p10 [START_REF] Sharma | The cell biology of 385 inflammasomes: mechanisms of inflammasome activation and 386 regulation[END_REF]; however, this view was recently challenged in an elegant study [START_REF] Boucher | Caspase-1 self-cleavage is an intrinsic 388 mechanism to terminate inflammasome activity[END_REF]. The authors demonstrated in mouse models that the dominant species of active CASP1 dimers, were in fact full-length p46 dimers and a transient species, p33/p10. In addition, p33/p10 autoprocessing occurred with kinetics specified by the inflammasome size and the cell type, resulting in the release of p20/p10 species, which became unstable, and protease activity was terminated [START_REF] Boucher | Caspase-1 self-cleavage is an intrinsic 388 mechanism to terminate inflammasome activity[END_REF]. Therefore, the inflammasome also incorporates an intrinsic self-limiting mechanism that ensures timely CASP1 deactivation [START_REF] Boucher | Caspase-1 self-cleavage is an intrinsic 388 mechanism to terminate inflammasome activity[END_REF].

Caspase dimerization and auto-proteolytic maturation lead to the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 [START_REF] Martinon | The inflammasome: a molecular plat-391 form triggering activation of inflammatory caspases and pro-392 cessing of proIL-beta[END_REF], and the induction of a form of programmed cell death called pyroptosis [START_REF] Lamkanfi | Mechanisms and functions 370 of inflammasomes[END_REF]. Pyroptosis leads to the loss of membrane integrity, which in turn, mediates the release of intracellular contents into the extracellular fluid [START_REF] Guo | Inflammasomes: mechanism of action, role 394 in disease, and therapeutics[END_REF]. Both IL-1β/18 release and pyroptosis are mediated by Gasdermin D (GSDMD) [START_REF] Kayagaki | Caspase-11 cleaves gasdermin D for 396 non-canonical inflammasome signalling[END_REF][START_REF] Shi | Cleavage of GSDMD by inflammatory 398 caspases determines pyroptotic cell death[END_REF].

In addition to its role in infection and inflammation, inflammasomes are also important in maintaining basic cellular functions, such as autophagy, metabolism, cellular proliferation, gene transcription, and tumorigenesis [START_REF] Rathinam | Inflammasome com-401 plexes: emerging mechanisms and effector functions[END_REF]. Recent findings have also indicated that inflammasomes play an essential role in the regulation of hematopoiesis in zebrafish, mouse, and human [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF][START_REF] Masters | NLRP1 inflammasome activation in-407 duces pyroptosis of hematopoietic progenitor cells[END_REF][START_REF] Ratajczak | NLRP3 inflammasome couples 410 purinergic signaling with activation of the complement cascade 411 for the optimal release of cells from bone marrow[END_REF][START_REF] Lenkiewicz | The Nlrp3 Inflammasome orches-414 trates mobilization of bone marrow-residing stem cells into 415 peripheral blood[END_REF][START_REF] Adamiak | Nlrp3 inflammasome signaling regu-417 lates the homing and engraftment of hematopoietic stem cells 418 (HSPCs) by enhancing incorporation of CXCR4 receptor into 419 membrane lipid rafts[END_REF][START_REF] Basiorka | The NLRP3 inflammasome functions 421 as a driver of the myelodysplastic syndrome phenotype[END_REF]. This is relevant, as uncontrolled inflammasome activation has led to certain human autoimmune and metabolic disorders, underscoring the importance of gaining a better understanding of this process in physiological and pathological contexts [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF].

Cell Type-Specific Inflammasomes

Neutrophils and monocytes/macrophages belong to the myeloid lineage originating from a common granulocyte-monocyte progenitor (GMP), which arises from the differentiation of HSCs [START_REF] Kondo | Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors[END_REF].

Neutrophils are the most abundant circulating leukocytes (50-70%) in most mammals, released from the bone marrow (BM) upon CXCL8, CXCL1, and CXCL2 chemokine signaling [START_REF] Mestas | Of mice and not men: differ-424 ences between mouse and human immunology[END_REF]. In a similar way, monocytes are released from the BM upon CCL2 and CCL7 signaling, via CCR2 [START_REF] Shi | Monocyte recruitment during in-427 fection and inflammation[END_REF]. Subsequently, they are extravasated by signals emanating from the activated endothelium close to inflamed tissues [START_REF] Gunzer | Traps and hyper inflammation -new ways 429 that neutrophils promote or hinder survival[END_REF][START_REF] Kolaczkowska | Neutrophil recruitment 432 and function in health and inflammation[END_REF][START_REF] Martínez-Navarro | Hydrogen peroxide in neutrophil 435 inflammation: lesson from the zebrafish[END_REF]. The production of neutrophils increases during infection or inflammation in a process called 'danger mobilization' or 'emergency hematopoiesis', mainly triggered by the hematopoietic cytokine granulocyte colony-stimulating factor (G-CSF) [START_REF] Köhler | G-CSF-mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands[END_REF].

Neutrophil and macrophage inflammasomes sense infection and sterile inflammation, through canonical and noncanonical pathways [START_REF] Kolaczkowska | Neutrophil recruitment 432 and function in health and inflammation[END_REF][START_REF] Bakele | Localization and functionality of the inflammasome in neutrophils[END_REF][START_REF] Yi | Regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory diseases[END_REF]. Both cell types express primarily a wide range of NLRs and ALRs, and are the first cells to participate in the inflammatory process [START_REF] Schroder | The inflammasomes[END_REF] (Table 1). Nonetheless, there are differences between inflammasomes in these cells, enabling the complex and specific regulation of cellular processes. Although they show similar amounts of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) and NOD-, LRR-, and CARD domain-containing protein 4 (NLRC4), the expression of NLRP12 is higher in mouse neutrophils than in macrophages [START_REF] Chen | The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge[END_REF]. The activation of NLRC4 in human macrophages occurs through specific Gram-negative bacteria components [START_REF] Mariathasan | Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf[END_REF][START_REF] Miao | Pseudomonas aeruginosa activates caspase 1 through Ipaf[END_REF]. Pyroptosis is induced in macrophages by ASC-independent NLRC4 signaling, or ASC-dependent NLRP3 and AIM2 inflammasome activation, facilitating the elimination of intracellular pathogens [START_REF] Broz | Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing[END_REF]. Even though NLRC4 or AIM2 signaling has also been observed in human and mouse neutrophils, they do not seem to induce pyroptosis [START_REF] Chen | The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge[END_REF]. Thus, neutrophils are quite resistant to pyroptosis and intracellular infection by bacteria [START_REF] Chen | The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge[END_REF]. Accordingly, they also engage in sustained release of IL-1ß, thus amplifying neutrophil recruitment and activation [START_REF] Chen | The neutrophil NLRC4 inflammasome selectively promotes IL-1beta maturation without pyroptosis during acute Salmonella challenge[END_REF]. Furthermore, when human neutrophil inflammasomes are activated by canonical agonists, IL-1ß,

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but not IL-1α and IL-18, is released, indicating that IL-1β and IL-18 protein release is differentially regulated in human neutrophils [START_REF] Bakele | Localization and functionality of the inflammasome in neutrophils[END_REF].

The NLRP3 inflammasome is involved in inflammatory and metabolic disorders as well as host defense [START_REF] Schroder | The inflammasomes[END_REF]. Although, it is also present in neutrophils, it acts differently. NLPR3 signaling in neutrophils is only activated through soluble agonists, but it can be triggered by soluble and particulate, or crystalline agonists in mouse macrophages [START_REF] Chen | The murine neutrophil NLRP3 inflammasome is activated by soluble but not particulate or crystalline agonists[END_REF]. In addition, NLRP3 activation leads to different cellular outcomes in macrophages and neutrophils. Both NLRP3/CASP1-dependent and NLRP3/CASP8-dependent inflammasomes lead to pyroptosis and apoptotic cell death in mouse macrophages, respectively, but not in neutrophils [START_REF] Pierini | AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages[END_REF][START_REF] Sagulenko | AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC[END_REF][START_REF] Chen | Cutting edge: blockade of inhibitor of apoptosis proteins sensitizes neutrophils to TNF-but not lipopolysaccharide-mediated cell death and IL-1beta secretion[END_REF].

Regarding hematopoietic stem and progenitor cells (HSPCs), the expression/activation of inflammasomes has received little attention. Nevertheless, the genes encoding the main components of the NLRP3 and NLRP1 inflammasome, including NLRP3, ASC, and CASP1, are expressed in human and mouse HSPCs [START_REF] Masters | NLRP1 inflammasome activation in-407 duces pyroptosis of hematopoietic progenitor cells[END_REF][START_REF] Adamiak | Nlrp3 inflammasome signaling regu-417 lates the homing and engraftment of hematopoietic stem cells 418 (HSPCs) by enhancing incorporation of CXCR4 receptor into 419 membrane lipid rafts[END_REF]. Similarly, nascent HSPCs in zebrafish embryos have been reported to express Asc [START_REF] Frame | Metabolic regulation of inflammasome activity controls embryonic hematopoietic stem and progenitor cell production[END_REF]. Therefore, each cell type shows different inflammasome components, activation mechanisms, and effector functions.

Inflammasomes in Diseases

Numerous data from mouse models, supported by human clinical data, strongly support the role of the inflammasome in the initiation and/or progression of diseases, with a strong impact on public health; these include certain metabolic disorders and neurodegenerative diseases [START_REF]Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever[END_REF]. However, the strongest evidence supporting a key role for inflammasomes in human pathology comes from numerous genetic association studies in a variety of diseases [START_REF] Van Opdenbosch | Caspases in cell death, inflammation, and disease[END_REF], consistent with their importance in the regulation of inflammation and tissue repair. The most convincing evidence comes from point mutations in a coding amino acid of the inflammasome sensors MEFV (coding for pyrin), NLRP3, and NLRP1, which lead to familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), and skin inflammatory and cancer susceptibility syndromes, respectively, highlighting the clinical significance of these proteins [START_REF]Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever[END_REF][START_REF] Consortium | A candidate gene for familial Mediterranean fever[END_REF][START_REF] Hoffman | Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome[END_REF][START_REF] Hoffman | Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever[END_REF][START_REF] Zhong | Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation[END_REF]. Furthermore, two recent studies demonstrated the presence of ASC specks in the serum of patients with chronic inflammatory disorders such as chronic obstructive pulmonary disease (COPD) and CAPS, and these might be considered as biomarkers of active disease [START_REF] Baroja-Mazo | The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response[END_REF][START_REF] Franklin | The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation[END_REF]. It is speculated that extracellular specks might also contribute to amplifying inflammation, as well as neutrophilia and anemia in human chronic inflammatory disorders such as these; it is possible that they might do so by altering the erythroid-myeloid fate decision of HSPCs [START_REF] Masters | NLRP1 inflammasome activation in-407 duces pyroptosis of hematopoietic progenitor cells[END_REF] when reaching the BM, but this remains to be demonstrated (see Clinician's Corner) (Figure 2, Key Figure ).

From another angle, the presence of neutrophils in atherosclerotic plaques correlates with the instability of these plaques, and a poor prognosis in atherosclerosis; this instability has also been associated with the formation of neutrophil extracellular traps (NETs) and inflammasome activation, since NETs have been detected in atherosclerotic lesions and arterial thrombi in humans and mice, and can induce the activation of endothelial cells, antigen-presenting cells, and platelets [START_REF] Döring | Neutrophil extracellular traps in atherosclerosis and atherothrombosis[END_REF][START_REF] Naruko | Neutrophil infiltration of culprit lesions in acute coronary syndromes[END_REF]. Moreover, both types of cellular death, pyroptosis and NETosis, need GSDMD cleavage; however, while mouse neutrophils use inflammasome-dependent mechanisms to cleave GSDMD and activate NETosis, human neutrophils use neutrophil elastase to do so [START_REF] Chen | Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps[END_REF][START_REF] Sollberger | Gasdermin D plays a vital role in the generation of neutrophil extracellular traps[END_REF]. Altogether, these observations suggest that chronic activation of macrophage and neutrophil inflammasomes can disrupt homeostasis in an organism and potentially contribute to inflammatory diseases; as such, inflammasomes might represent promising therapeutic targets for restoring homeostasis in a variety of pathologies, but this evidently remains to be further investigated. 160 It is the only vertebrate model that has the main advantages of invertebrates (e.g., the fruit fly and 161 Caenorhabditis elegans), including: (i) high fecundity (between 200 and 300 eggs per female can 162 be obtained each week), and the embryonic development is rapid and external; (ii) the embryos 163 are transparent, allowing the development and tracking of their cells in tissues and organs 164 using optical and fluorescent methods; and (iii) the animal is suitable for high throughput chemical 165 and genetic screenings [START_REF] Santoriello | Hooked! Modeling human disease in zebrafish[END_REF]. In addition, its genome is completely sequenced and shares 70% of 166 its genes with humans, where up to 82% of them are known to be relevant/causative of human 167 diseases [START_REF] Howe | The zebrafish reference genome sequence and its relationship to the human genome[END_REF]. This high genetic homology allows transgenesis studies with human genes and en-168 ables the in vivo study of gene regulation and function.

169 Zebrafish have been used as a research model to study hematopoiesis [START_REF] Ellett | Zebrafish as a model for ver-513 tebrate hematopoiesis[END_REF]. Although hemato-170 poiesis in zebrafish occurs in sites that are distinct from other vertebrates (e.g., zebrafish HSCs 171 reside in the kidney marrow), the genetic programs controlling hematopoiesis are conserved Pyroptosis: highly inflammatory form of programmed cell death promoted by inflammasomes. Specks: large protein complex of ASC formed after inflammasome activation. SPI1: transcription factor regulating the expression of genes involved in myelopoiesis and B lymphocyte development.

Transcription activator-like effector nucleases (TALENs): restriction enzymes that can be engineered to cut specific sequences of DNA. HSPCs GATA1 cleavage Zebrafish [START_REF] Masters | NLRP1 inflammasome activation in-407 duces pyroptosis of hematopoietic progenitor cells[END_REF] t1:6

GATA1 cleavage

Human Mouse [START_REF] Masters | NLRP1 inflammasome activation in-407 duces pyroptosis of hematopoietic progenitor cells[END_REF] t1:7

Pyroptosis Mouse [START_REF] Ratajczak | NLRP3 inflammasome couples 410 purinergic signaling with activation of the complement cascade 411 for the optimal release of cells from bone marrow[END_REF] t1:8

HSPC mobilization and engraftment Mouse [START_REF] Lenkiewicz | The Nlrp3 Inflammasome orches-414 trates mobilization of bone marrow-residing stem cells into 415 peripheral blood[END_REF][START_REF] Adamiak | Nlrp3 inflammasome signaling regu-417 lates the homing and engraftment of hematopoietic stem cells 418 (HSPCs) by enhancing incorporation of CXCR4 receptor into 419 membrane lipid rafts[END_REF][START_REF] Basiorka | The NLRP3 inflammasome functions 421 as a driver of the myelodysplastic syndrome phenotype[END_REF] t1:9

Erythroid progenitors GATA1 cleavage for terminal erythroid differentiation Human [START_REF] Masters | NLRP1 inflammasome activation in-407 duces pyroptosis of hematopoietic progenitor cells[END_REF] t1:10

Mature myeloid cells

IL-1β and IL-18 cleavage Pyroptosis

Human Mouse [START_REF] Pilla | Guanylate binding proteins promote 372 caspase-11-dependent pyroptosis in response to cytoplasmic 373 LPS[END_REF] t1:11

IL-1β and IL-18 cleavage Pyroptosis

Human Mouse [START_REF] Pilla | Guanylate binding proteins promote 372 caspase-11-dependent pyroptosis in response to cytoplasmic 373 LPS[END_REF] t1:12

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between zebrafish and mammals, including humans, making zebrafish a clinically relevant model system [4]. The earlier mentioned advantages, together with the construction of detailed genomic databases, have allowed a series of genetic approaches to be used in this model for the study of a variety of blood disorders, such as congenital and acquired anemia, neutrophilia, and leukemia [START_REF] Berman | The zebrafish as a tool to study hemato-515 poiesis, human blood diseases, and immune function[END_REF]. Zebrafish has also consolidated its position as a powerful animal model in the fields of immunity, inflammation, and infection [START_REF] Yoshida | Macrophage-microbe interactions: 518 lessons from the zebrafish model[END_REF][START_REF] Renshaw | A model 450 million years 520 in the making: zebrafish and vertebrate immunity[END_REF]. It has contributed to improving our knowledge of human infections, such as tuberculosis which is difficult to model in vivo in mammals [START_REF] Meijer | Protection and pathology in TB: learning from 523 the zebrafish model[END_REF]. In addition, the optical transparency of the early life stages of zebrafish offers unprecedented possibilities for studying the activation and dynamics of inflammasomes in vivo [START_REF] Kuri | Dynamics of in vivo ASC speck formation[END_REF].

Gain (mRNA) and loss of function experiments in embryos [morpholinos, transcription activator-like effector nucleases (TALEN) and CRISPR-Cas technologies] are relatively simple to perform, enabling the study of the role of specific molecules, including those involved in the inflammasome, and these roles have been better deciphered using different stimuli and pathogens [START_REF] Renshaw | A model 450 million years 520 in the making: zebrafish and vertebrate immunity[END_REF]. In addition, zebrafish has allowed the analysis and visualization of different types of immune cells, including neutrophils and macrophages; indeed, the assembly of inflammasomes has been studied using transgenic zebrafish lines that are either already available, Trends in Immunology

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or easy to generate [START_REF] Meijer | Host-pathogen interactions 527 made transparent with the zebrafish model[END_REF]. Among the numerous transgenic lines available to study hematopoiesis and inflammasomes, the following should be mentioned (Figure 3): Tg(mpx:eGFP) [START_REF] Renshaw | A transgenic zebrafish model of neu-530 trophilic inflammation[END_REF] and Tg(lyz: dsRed) [START_REF] Hall | The zebrafish lysozyme C promoter drives 532 myeloid-specific expression in transgenic fish[END_REF], which express fluorescent eGFP or dsRed driven by the neutrophil specific Tissue-specific inhibition of inflammasome using the GAL4/UAS system.

Tg(UAS:ascΔCARD-eGFP)

Asc recruits Caspase a AscΔCARD-eGFP does not recruit Caspase a Tissue-specific activation of inflammasome using the GAL4/UAS system.

Tg(uas:gbp4) Knock-in transgenic line in which the endogenous Asc is fused with eGFP. Specific hematopoietic cell types and the visualization of the inflammasome assembly in real time have been feasible using these lines [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF][START_REF] Kuri | Dynamics of in vivo ASC speck formation[END_REF] . Chemical and genetic screening methods are also amenable in zebrafish, sharing certain advantages of invertebrate models for high throughput screening and in vivo imaging, such as high fecundity, optical transparency, and rapid and external development. Abbreviations Q2 : ASC, apoptosis-associated speck-like protein containing a CARD; HSPCs, hematopoietic stem and progenitor cells; PYD, pyrin domain.

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promoters myeloperoxidase and lysozyme, respectively; Tg(mpeg1:eGFP) [START_REF] Ellett | mpeg1 promoter transgenes direct 535 macrophage-lineage expression in zebrafish[END_REF], with labeled macrophages stemming from activation of the mpeg1 promoter; and Tg(lcr:eGFP) [START_REF] Ganis | Zebrafish globin switching occurs in two 538 developmental stages and is controlled by the LCR[END_REF] which has green fluorescent erythrocytes due to the expression of eGFP, driven by a globin regulatory sequence. Moreover, another two lines can be used to study erythropoiesis: Tg(gata1:DsRed) [START_REF] Traver | Transplantation and in vivo imaging of 541 multilineage engraftment in zebrafish bloodless mutants[END_REF], which allows visualization of erythroid cells because they express dsRed driven by the gata1 promoter; and Tg(runx1:GAL4) [START_REF] Tamplin | Hematopoietic stem cell arrival triggers dynamic remodeling of the perivascular niche[END_REF] with its labeled HSPCs. Finally, the knock-in line Tg (asc:asc-eGFP) allows real-time single cell visualization of inflammasome assembly [START_REF] Masters | NLRP1 inflammasome activation in-407 duces pyroptosis of hematopoietic progenitor cells[END_REF], and the lines Tg(uas:ascΔCARD-eGFP

Q9

) and Tg(uas:gpb4) allow the respective inhibition or activation of the inflammasome in specific cell types [START_REF] Chen | Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps[END_REF].

The Zebrafish Model Sheds Light on the Importance of the Inflammasome in Hematopoiesis

As mentioned, a relationship between inflammasome activation and hematopoiesis has been suggested for several medical conditions; for instance, hematopoietic lineage bias has been associated with chronic inflammatory diseases. However, the mechanisms and signaling pathways involved are unknown. One of the first pieces of evidence for this was the demonstration that human GATA1 could be cleaved in vitro by many caspases, and in vivo by caspase-3 in human erythroid precursors [START_REF] De Maria | Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1[END_REF][START_REF] Ribeil | Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1[END_REF]. Furthermore, the activation of Nlrp1a in mouse HSPCs triggers pyroptotic death of these cells and leukopenia in the absence of inflammation, while in periods of hematopoietic stress induced by chemotherapy or viral infection, NLRP1a activation caused prolonged cytopenia, BM hypoplasia, and immunosuppression [START_REF] Masters | NLRP1 inflammasome activation in-407 duces pyroptosis of hematopoietic progenitor cells[END_REF]. In addition, the Trends Trends in in Immunology Immunology Figure 4. Zebrafish Disease Models for Studying Hematopoiesis. In homeostasis conditions, embryonic hematopoiesis takes place in the caudal hematopoietic tissue (CHT) 2-3 days postfertilization (middle panel). The Spint1a-deficient line (spint1a hi2217Tg/hi2217Tg ) is an excellent model for studying hematopoietic lineage bias associated with chronic inflammation, since it leads to neutrophilia which can be visualized (left panel). The Gata1 amorphant animal is an amenable model of Diamond-Blackfan anemia. In both models, inhibition of the inflammasome can rescue hematopoietic lineage bias [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF]. Abbreviation: HSPCs, hematopoietic stem and progenitor cells.

U N C O R R E C T E D P R O O F
NLRP3 inflammasome is required for the optimal release of mouse HSPCs from the BM in response to purinergic signaling, complement activation, and G-CSF administration [START_REF] Ratajczak | NLRP3 inflammasome couples 410 purinergic signaling with activation of the complement cascade 411 for the optimal release of cells from bone marrow[END_REF][START_REF] Lenkiewicz | The Nlrp3 Inflammasome orches-414 trates mobilization of bone marrow-residing stem cells into 415 peripheral blood[END_REF]. Notably, transplantation experiments in mouse have shown that NLRP3 knockout, either in HSPCs or in BM stromal cells, results in impaired HSPC homing and engraftment [START_REF] Adamiak | Nlrp3 inflammasome signaling regu-417 lates the homing and engraftment of hematopoietic stem cells 418 (HSPCs) by enhancing incorporation of CXCR4 receptor into 419 membrane lipid rafts[END_REF]. Furthermore, the NLRP3 inflammasome has been found to drive clonal expansion and pyroptotic cell death in myelodysplastic syndrome patients [START_REF] Basiorka | The NLRP3 inflammasome functions 421 as a driver of the myelodysplastic syndrome phenotype[END_REF] (see Clinician's Corner). Accordingly, it has been demonstrated that, while the canonical inflammasome is dispensable for HSPC emergence in zebrafish larvae, it autonomously regulates HSPC differentiation in homeostatic conditions at two different levels: erythroid-myeloid cell fate decision and terminal erythroid differentiation [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF] (Figure 1 and Table 1). Thus, the genetic or chemical inhibition of different inflammasome components, {e.g., Gbp4 [Tg(uas:gpb4)], Asc Tg(uas:ascΔCARD-eGFP)], or caspase a (Caspa)}, (the zebrafish functional equivalent of pharmacological inhibition of mammalian CASP1), resulted in a decreased number of neutrophils and macrophages accompanied by a concomitant increase in erythrocyte counts in larvae, while conversely, the forced expression of both Asc and Caspa simultaneously by mRNA injection, increased neutrophil numbers [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF]. These results were further confirmed by neutrophil ablation experiments, achieved by treating larvae, which express the bacterial nitroreductase in neutrophils with the prodrug metronidazole; pharmacological inhibition of CASP1 fully impaired neutrophil recovery after ablation. Further analysis showed that the emergence of HSPCs in Tg(runx1:GAL4) was not affected, suggesting that the inflammasome could regulate HSPC differentiation [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF]. Mechanistically, inflammasome activation in HSPCs resulted in reduced Gata1 protein amounts, enforcing myelopoiesis and inhibiting erythropoiesis. The mechanism seems to be evolutionarily conserved, since the pharmacological inhibition of CASP1 in HSCs from SPI1-eYFP and GATA1-mCherry reporter mice rapidly increased Gata1 protein amounts, without affecting those of Spi1, resulting in increased erythroid differentiation at the expense of myeloid differentiation (Figure 1) [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF]. In addition, erythroid differentiation of the human erythroleukemic line K562 was also impaired upon inhibition of CASP1, but not CASP4, suggesting a role for the canonical inflammasome in terminal erythroid differentiation, by dampening GATA1 protein amounts [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF]. In vitro experiments confirmed the ability of human recombinant CASP1 to cleave GATA1 at residue D300 [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF]. Taken together, these results support a scenario in which GATA1 protein amounts are fine-tuned by the canonical inflammasome in HSPCs, to regulate the erythroid-myeloid decision, and simultaneously in erythroid progenitors, to regulate their terminal differentiation. Furthermore, the inflammasome and macrophage-derived IL-1β Q10 appear to be required for the expansion of HSPCs of zebrafish embryos, assayed by whole-mount in situ hybridization of the HSPC markers runx1/cmyb and Tg (cd41:eGFP) larvae [START_REF] Hoffman | Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever[END_REF]. Further studies are required, however, to elucidate the signals responsible for activating the inflammasome in HSPCs in homeostasis, as well as the inflammasome components involved (see Outstanding Questions). This close relationship between GATA1 and CASP1 is relevant at a clinical level, since bias of the hematopoietic lineage has been associated with a higher incidence of diseases with an inflammatory component, such as infection, rheumatoid arthritis, atherosclerosis, inflammatory bowel diseases, kidney and pulmonary diseases, autoimmune pathologies, neurodegenerative diseases, and certain cancers [START_REF] Elias | Molecular mechanisms underlying line-368 age bias in aging hematopoiesis[END_REF]. An example of this group of diseases is neutrophilic dermatosis, characterized by the accumulation of neutrophils in polymorphic cutaneous lesions of patients [START_REF] Marzano | A comprehensive review of neutrophilic diseases[END_REF]. A zebrafish line deficient in the serine peptidase inhibitor, Kunitz type 1a (Spint1a), has been used as a model of this disease, since it shows neutrophilia, skin lesions, and high skin neutrophil infiltration [START_REF] Carney | Inactivation of serine protease Matriptase1a by its inhibitor Hai1 is required for epithelial integrity of the zebrafish epidermis[END_REF][START_REF] Mathias | Live imaging of chronic inflammation caused by mutation of zebrafish Hai1[END_REF]. Accordingly, inhibition of the canonical inflammasome with the CASP1 inhibitor Ac-YVAD-CMK in this model, restored Gata1 amounts and decreased the number of neutrophils, even though both skin lesions and neutrophil infiltration were not affected [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF] (Figure 4).

Clinician's Corner

Alterations in inflammasome activity might have important clinical implications, since hematopoietic lineage bias has been associated with certain chronic diseases with prominent inflammatory components, including infections, rheumatoid arthritis, atherosclerosis, inflammatory bowel diseases, kidney and pulmonary diseases, autoimmune conditions, neurodegenerative diseases, and cancer [START_REF] Elias | Molecular mechanisms underlying line-368 age bias in aging hematopoiesis[END_REF][START_REF] Marzano | A comprehensive review of neutrophilic diseases[END_REF][START_REF] Wu | Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients[END_REF].

Emerging evidence suggests that the inflammasome may play a key role in a variety of human diseases, including FMF, CAPS, and skin inflammatory and cancer syndromes, which are driven by gain-of-function mutations in MEFV, NLRP3, and NLRP1, respectively [START_REF]Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever[END_REF][START_REF] Consortium | A candidate gene for familial Mediterranean fever[END_REF][START_REF] Hoffman | Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome[END_REF][START_REF] Hoffman | Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever[END_REF][START_REF] Zhong | Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation[END_REF]. As many FMF and CAPS patients develop iron-resistant hypochromic anemia, inflammasome overactivation in HSPCs might contribute to anemia, which might explain its iron-refractory nature, although this warrants further investigation.

NLRP3 and ASC specks are present in the serum of CAPS and COPD patients, and might be considered as putative biomarkers of active disease [START_REF] Baroja-Mazo | The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response[END_REF][START_REF] Franklin | The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation[END_REF]. These specks might contribute to amplifying not only inflammation, but also neutrophilia and anemia, after being taken up by HSPCs, activating their inflammasome, and promoting hematopoietic lineage bias through GATA1 cleavage and inactivation. This also requires further testing.

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U N C O R R E C T E D P R O O F
Another disease in which inhibition of the canonical inflammasome might be considered a putative therapeutic target for further exploration is Diamond-Blackfan anemia (DBA), a hereditary disease in which erythropoiesis is impaired due to reduced GATA1 protein amounts [START_REF] Ludwig | Altered translation of GATA1 in Diamond-Blackfan anemia[END_REF]. We modeled DBA in zebrafish by reducing Gata1 amounts using a specific morpholino [START_REF] Danilova | The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia[END_REF]. Pharmacological inhibition of Caspa with Ac-YVAD-CHO in this DBA model was able to partially rescue anemia and to increase Gata1 and to decrease Spi1 protein amounts [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF] (Figure 4). Taken together, pharmacological inhibition of the inflammasome rescued neutrophilic inflammation and anemia in these zebrafish disease models [START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF]; this suggested that the inflammasome can play a major role in hematopoietic lineage bias during certain chronic inflammatory diseases and DBA, at least stemming from zebrafish models. Nevertheless, these findings certainly merit further attention in identifying novel druggable targets for potential therapeutic interventions in some of these conditions (see Clinician's Corner).

Concluding Remarks

The zebrafish model has unique advantages for biomedical research and, herein discussed is its relevance for designing studies to better understand the roles and mechanisms of inflammasome activation in hematopoiesis. The availability of models of chronic inflammatory diseases, including neutrophilic dermatosis and rare diseases such as DBA, provides an excellent and unique tool to rapidly identify novel treatments for some of these pathologies, and furthermore, for screening clinically approved drug libraries that may facilitate relatively rapid repurposing. In addition, powerful CRISPR-Cas9 technology allows the rapid generation of candidate pathogenic mutations, which can even be analyzed in the F0 generation without the need for generating timeconsuming deficient lines, to confirm their pathogenicity, and target or lead drug screening (see Clinician's Corner). Finally, it is essential to find the specific inflammasome(s) involved in hematopoiesis to develop more specific treatments for the hematopoietic lineage bias associated with chronic inflammatory disorders (see Outstanding Questions). The possibility of in vivo tracking of hematopoietic cells, together with the inflammasome tools available, including reporters to visualize its assembly in real time, can make this model complementary to other models of vertebrate species, to study the crosstalk between hematopoiesis and inflammation in general, and the inflammasome in particular. In what ways can zebrafish models significantly complement other animal models to further elucidate many of these questions?

b0: 2 Box 1 . 3 Familiar

 213 Anemia-Associated with FMF and CAPS b1:Mediterranean Fever (FMF) and cryopyrin-associated periodic syndrome (CAPS) are two inflammatory diseases b1:4

158

  The Zebrafish: A Unique Model for Studying Hematopoiesis and Inflammation 159 The zebrafish has become an exceptional model organism in many fields of biomedical research.

t1: 2 (

 2 Macrophages and Neutrophils) in the Indicated Species a,b

. t1: 13 a

 13 Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase activation and recruitment domains; CASP1, caspase 1; GBP, guanylate-t1:14 binding proteins; GSDMD, Gasdermin D; HSPCs, hematopoietic stem and progenitor cells; NLRs, nucleotide-binding domain-like receptors; PYD, pyrin domain.t1:15 b The domains of each inflammasome component are shown.

Proposed

  Figure 2. (A) In this model, based largely on zebrafish studies, macrophages and neutrophils are recruited to inflamed tissues, for example the skin, where they are activated by different proinflammatory signals. Activation of the inflammasome results in ASC speck release into the circulation. (B)Blood-borne specks that can reach the hematopoietic tissue (bone marrow in mammals and kidney marrow in zebrafish), are taken up by HSPCs or resident macrophages, and activate their inflammasome, leading to IL-1β/IL-18 release, GATA1 cleavage, reduced erythropoiesis, and increased myelopoiesis[START_REF] Tyrkalska | Inflammasome regulates hemato-404 poiesis through cleavage of the master erythroid transcription 405 factor GATA1[END_REF][START_REF] Baroja-Mazo | The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response[END_REF][START_REF] Franklin | The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation[END_REF]. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; HSPCs, hematopoietic stem and progenitor cells; IL, interleukin.

TgFigure 3 .

 3 Figure 3. Zebrafish Transgenic Lines in the Study of Inflammation and the Inflammasome in Hematopoiesis.

  lineages. Immunity 19, 451-462 Outstanding Questions What signals are responsible for activating the inflammasome in HSPCs? What is the cellular source of these signalsdo they have a stromal or hematopoietic origin? Are the signals activating the HSPC inflammasome the same in steady state and inflammatory conditions? What are the components of the HSPC inflammasome? Does ASC form specks upon activation of the HSPC inflammasome? Which kind of specks? Are these specks able to activate GSDMD? What are the respective contributions of IL-1β/IL-18 release, pyroptotic cell death, and GATA1 cleavage to HSPC and erythroid precursor differentiation? Besides IL-1β, IL-18, GSDMD, and GATA1, are other proteins cleaved by the inflammasome in HSPCs in steady state and inflammatory conditions?Since activated macrophages can release specks that activate bystander cells, are these specks able to reach the BM and modulate the activation of the HSPC inflammasome in inflammatory conditions?

  Whyatt, D. et al. (2000) An intrinsic but cell-nonautonomous 363 defect in GATA-1-overexpressing mouse erythroid cells. Nature

Table 1 .

 1 Components and Effector Functions of the Main Canonical Inflammasomes in HSPCs, Erythroid Progenitors, and Mature Myeloid Cells

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Acknowledgments

The work in our laboratory is funded by the Spanish Ministry of Science and Innovation (grant BIO2017-84702-R to V.M.) and PhD fellowship to L.R-R., both cofunded with Fondos Europeos de Desarrollo Regional/European Regional Development Funds, ISCIII-CIBERER (grant CB19/07/00031 to V.M.), Fundación Séneca, Agencia de Ciencia y Tecnología de la Región de Murcia (grant 20793/PI/18 to V.M.), and the University of Murcia (postdoctoral contract to D.G-M.).