HSPCs give rise to all types of blood cells and play a pivotal role in building the immune system. As suggested by its former name (multi-colony stimulating factor), IL-3 stimulates the growth and differentiation of HSPCs from bone marrow cultures and in naive or sublethally irradiated mice into a large range of cell lineages, including basophils, neutrophils, eosinophils, macrophages, erythroid cells, megakaryocytes, and dendritic cells (DCs) (48, 49). Despite the abovementioned ability of IL-3 to stimulate hematopoiesis, mice deficient for Il-3 exhibit normal hematopoiesis under physiological conditions (33) indicating that IL-3 is not essential for the development of all blood cell lineages at steady state. However, IL-3 was described to play a key role in splenic extramedullary hematopoiesis during inflammatory diseases (2, 10, 40), which is consistent with the ability of recombinant IL-3 to increase hematopoiesis in the spleen and the liver of naive mice but not in the bone marrow (48, 49). Likewise, IL-3 increases the number of tissue mast cells and enhances basophil production during parasite infection, while it is dispensable for their generation under physiological conditions (33), thus making IL-3 an orchestrator of emergency hematopoiesis.

Eosinophils are polymorphonuclear cells involved in the protection against multicellular parasites through the release of a variety of granular mediators and the production of toxic reactive oxygen species (50). IL-3 induces eosinophil survival (51) and is associated with early and end stages of eosinophilic differentiation and maturation (52). In addition, IL-3 increases human eosinophil adhesion, chemotaxis and migration (53) and stimulates cytotoxicity against antibody-sensitized helminths, superoxide anion production and phagocytosis of opsonized yeast particles (54).

Basophils, one of the main effector cells during allergic diseases, are described to express both IL-3 (55) and its receptor (56). As for eosinophils, IL-3 plays a key role in basophil survival, migration and activation. Indeed, IL-3 protects basophil from apoptosis in vitro in a Pim1-dependent manner (57), increases basophil number in the blood during parasite infection (34), and enables basophil extravasation during allergic contact dermatitis (58). Moreover, IL-3, alone or in a combination with other molecules, such as anti-FcϵRI mAb, complement component 5a, N-Formylmethionine-leucyl-phenylalanine (fMLP), CCL2 or eotaxin, enhances the expression of various immune mediators important for the function of basophils, such as histamine (59) or granzyme B (60).

In mice, IL-3 promotes mast cell growth and differentiation (61) and enhances mediator release (62). However, CD123 was not detected on human mast cells purified from tonsils, lungs, uterus and skin (63) and no IL-3-binding sites were detected on enriched human lung mast cells (64) suggesting a limited impact of IL-3 on human mature mast cells in vivo.

In steady-state, murine monocytes and human classical monocytes do not express the receptor for IL-3. Only human intermediate and non-classical monocytes express it (65). Although IL-3 alone does not seem to modulate the function of CD14⁺ monocytes, in vitro experiments show that IL-3 synergizes with IL-4 to enhance CCL17 expression in CD14⁺ monocytes, a marker of alternative activation, IL-4 increasing the responsiveness to IL-3 by inducing CD123 expression (66). Likewise, IL-3 enhances the production of TNFα by CD14⁺ monocytes upon lipopolysaccharide (LPS) stimulation by modulating TNFα posttranscriptional levels (67). In combination with IFNβ or IL-4, IL-3 drives the differentiation of CD14⁺ monocytes into DCs exhibiting pro- or anti-inflammatory properties, respectively (68, 69), and IL-3 induces the expression of the lectins mannose receptor, Dectin-1, and DC-SIGN during monocyte-derived macrophage differentiation allowing increased phagocytosis (70). Besides this, IL-3 modulates the expression of IL-1 and the chemokines CCL2, CCL3, CCL7, CCL12 in macrophages (8, 71, 72), increases peritoneal macrophage phagocytic activity (48), and elicits transcriptional, morphological, and functional programming of microglia (1, 14).

In addition to the monocyte-macrophage compartment, it was described that human pDCs express high levels of CD123, whereas murine pDCs do not express it (73). In humans, IL-3 promotes the survival of pDCs (74) as well as their differentiation in a sub-population of DCs characterized by a low ability to produce type I and III interferons but with a high capacity to prime T cells (27, 28). Interestingly, recent studies have revealed that CD123 is not only expressed on human pDCs but also on AXL⁺ DCs, dendritic cell precursors that look similar to conventional DC2s in terms of basic function and morphology (75).

T cells are a major source of IL-3 during inflammation (76) and IL-3-producing T cells are involved in many inflammatory and infectious diseases. In humans, CD123 is expressed on activated CD4⁺ and CD8⁺ T cells (77). Exposure to IL-3 enhances T cell proliferation and survival (77), inhibits Th17 differentiation (19) and enhances Th2 differentiation as well as IL-4, IL-5, and IL-13 expressions (78). Moreover, IL-3 promotes the differentiation of naive CD4⁺ T cells into regulatory T cells, and modulates regulatory T cell migration by modifying their actin cytoskeleton structure (43). Like T cells, activated human B cells express CD123 and IL-3 supports their proliferation and survival (77). In addition, IL-3 enhances IgG and IL-6 secretions but reduces IL-10 expression (77, 79). Recently, innate response activator (IRA) B cells, a subset of B-1a B cells residing in serosal sites, have been described as a source of IL-3 in infectious and inflammatory diseases (2, 40). After activation, IL-3-producing IRA B cells accumulate in the spleen, where they fuel the immune response by promoting extramedullary hematopoiesis (2, 40).

In addition to hematopoietic cells, CD123 is expressed by endothelial and epithelial cells (2, 29). IL-3 induces intestinal epithelial cell proliferation (80) and stimulates CXCL12 expression in lung epithelial cells (29), while it promotes endothelial cell proliferation and motility in vitro (81, 82) as well as new vessel formation and tumor angiogenesis in vivo (82). Moreover, IL-3 induces the expression of adhesion molecules and chemokines in endothelial cells, thereby promoting immune cell rolling, adhesion, and transmigration (81).

IL-3 plays an important role in bones by directly targeting both osteoblasts and osteoclasts. IL-3 promotes the differentiation of human mesenchymal stem cells into osteoblasts (83) and stimulates the formation and the survival of mononuclear osteoclasts (84). However, IL-3 inhibits the formation of mature multinucleated osteoclasts by diverting osteoclast precursors into macrophage or dendritic cell lineages, inhibiting NF-kB nuclear translocation induced by RANKL, and downregulating the expression of c-Fms (20, 21).

Cardiovascular diseases are a group of disorders of the heart and blood vessels that are a leading cause of mortality worldwide (85). Although IL-3 is hardly detected in the heart in steady-state, its expression increased significantly during autoimmune myocarditis (8) and allograft heart transplantation (9). IL-3 is also expressed in early and advanced atherosclerotic plaques in humans (11) and plasma IL-3 levels predict for symptomatic restenosis (86). In experimental autoimmune myocarditis, IL-3 amplifies cardiac inflammation by promoting CCR2⁺ Ly-6C^high monocyte accumulation in the heart via the stimulation of tissue macrophages. Recruited monocytes give rise to APCs that enhance local T cell proliferation and T cell-derived cytokine production, including IL-3, thus amplifying local inflammation (8). In addition, deletion or inhibition of IL-3 reduced the development of myocardial fibrosis and protects from chronic rejection of heart transplants by reducing the ability of infiltrating basophil to secrete IL-4 and IL-6 (9). In atherosclerosis, IL-3 sustains both the proliferation and the migration of vascular smooth muscle cells (11), a major source of plaque cells and extracellular matrix at all stages of atherosclerosis (87). Interestingly, IL-3 secreted in the spleen of Apoe^-/- mice promotes HSPC expansion and differentiation into Ly6C^high monocytes. Monocytes born in such extramedullary niches intravasate, circulate, and accumulate abundantly in atherosclerotic lesions where they secrete inflammatory cytokines, reactive oxygen species and proteases, and eventually become foam cells (10), thus promoting atheroma macrophage burden (12). Therefore, IL-3 seems to modulate inflammation in cardiac and vascular tissue by exerting its activity directly at the inflammatory site and indirectly in periphery.

Studies investigating the contribution of IL-3 in asthma pathogenesis, a chronic inflammatory disorder associated with airway hyper-responsiveness, show inconsistent results, both on IL-3 expression levels and function. Indeed, IL-3 levels were found either increased in sputum (93) and BALF (94) of asthmatic patients, reduced in nasopharyngeal fluid of asthmatic children (30), or similar in bronchial biopsies between asthmatic and non-asthmatic patients (95). Likewise, a report showed that mice deficient for Il-3 exhibit increased pulmonary inflammation during asthma, characterized by local eosinophil infiltration and increased secretion of IgE, IL-5, and IL-13 (31). On the contrary, another study reported that Il-3 ^-/- mice show similar number of basophils and eosinophils in BALF as well as similar serum IgE levels when compared to control mice (32). In human, it was shown that (i) sputum IL-3 secretion correlates with levels of eosinophil granule proteins and decreased lung function (93); (ii) IL-3⁺ BALF cells are associated with asthma severity (96) and; (iii) serum IL-3 levels are higher in patients with uncontrolled chronic asthma (97). By contrast, other studies revealed that IL-3 produced by PBMCs is associated with amelioration of asthma in pre-school children (31) and that IL-3 expression in lung tissue is not correlated with eosinophil and metachromatic cell number, airway responsiveness, or the severity of the late asthmatic response (95). Mechanistically, IL-3 was described to protect against asthma by reducing the number of innate lymphoid cell type 2 in lungs and by increasing regulatory T cell number in the airways (30, 31). On the other hand, IL-3 was reported to be detrimental in asthma by enhancing the secretion of histamine and Th2 cytokines by basophils (32). This contradictory effect in mice might result from the different times of injection, application routes, and doses of IL-3, while the differences observed in humans might be explained by the age of the patients (children vs adults) or the stage of the disease.

Inflammatory bowel diseases (IBDs) are inflammatory disorders of the intestinal tract characterized by in an aberrant mucosal immune response driven by microbial factors of the commensal gut microbiota (100). Whereas the role of GM-CSF during colitis is clearly established, the role of IL-3 was until recently unknown. IL-3 and CD123 expressions are upregulated in inflamed tissue of patients with IBDs and correlate with the levels of inflammation (2, 43). In the colon, IL-3 is produced by T cells and cells harboring a mesenchymal stem cell phenotype, whereas CD123 is expressed by epithelial and infiltrating immune cells (2, 43). The use of different models of colitis has revealed that IL-3 has a dual role during acute colitis, which seems to depend on the intensity of the inflammation. On the one hand, IL-3 protects by (i) promoting the early recruitment of splenic neutrophils with high microbicidal capacity in the colon, which requires CCL5⁺ PD-1^hi LAG-3^hi T cells, STAT5 signaling, and CCL20 (2); (ii) preventing the egress of regulatory T cells from the colon through the modification of their actin cytoskeleton structure (43) and; (iii) stimulating the proliferation of basophils, which protects from acute inflammation by reducing the expression of IFNγ, IL-2, and TNFα in T cells (44). On the other hand, it was reported that IL-3 increases colitis severity during the acute phase of colitis by amplifying colonic inflammation (2). This phenomenon might result from the ability of IL-3 to promote extramedullary hematopoiesis in the spleen during colitis (2), which is important at the onset of the disease to sustain splenic neutrophil emigration into the colon, but might become detrimental during acute colitis by fueling the inflammatory immune response.