IL-33–Induced Hematopoietic Stem and Progenitor Cell Mobilization Depends upon CCR2

Abstract

IL-33 has been implicated in the pathogenesis of asthma, atopic allergy, anaphylaxis, and other inflammatory diseases by promoting the production of proinflammatory cytokines and chemokines or Th2 immune responses. In this study, we analyzed the in vivo effect of IL-33 administration. IL-33 markedly promoted myelopoiesis in the bone marrow and myeloid cell emigration. Concomitantly, IL-33 induced hematopoietic stem and progenitor cell (HSPC) mobilization and extramedullary hematopoiesis. HSPC mobilization was mediated mainly through increased levels of CCL7 produced by vascular endothelial cells in response to IL-33. In vivo treatment of IL-33 rapidly induced phosphorylation of ERK, JNK, and p38, and inhibition of these signaling molecules completely blocked the production of CCL7 induced by IL-33. Consistently, inhibitor of CCR2 markedly reduced IL-33–mediated HSPC mobilization in vivo and migration of HSPCs in response to CCL7 in vitro. IL-33–mobilized HSPCs were capable of homing to, and of long-term reconstitution in, the bone marrow of irradiated recipients. Immune cells derived from these recipients had normal antifungal activity. The ability of IL-33 to promote migration of HSPCs and myeloid cells into the periphery and to regulate their antifungal activity represents a previously unrecognized role of IL-33 in innate immunity. These properties of IL-33 have clinical implications in hematopoietic stem cell transplantation.

IL-33 Enhances Host Tolerance to Candida albicans Kidney Infections through Induction of IL-13 Production by CD4+ T Cells

“…In a previous study, we found that IL-33 can increase neutrophil phagocytic activity in a peritoneal C. albicans infection (13,14). In the current study, an in vivo phagocytosis assay demonstrated that IL-33-primed CD11b + Ly6G hi neutrophils had a higher capacity to phagocytose FITC-labeled C. albicans in kidneys at 1 d postinfection (Fig.…”

“…However, infusion of large amounts of IL-33 could suppress immunopathology potently in two ways: by effective early fungal clearance and by inducing Th2 immunity, which has an anti-inflammatory effect. This dual action of IL-33 was a surprise, because in a previous study of a model of Candida sepsis we found that IL-33 potentiates neutrophil infiltration into peritoneum via the production of CXCR2 chemokines by macrophages (13,14). Thus, it appears that IL-33 has evolved functionally to provide a strategy whereby the kidney protects itself from damage by pathogens and immunopathology.…”

“…In fact, IL-33 was shown to enforce TLR and Dectin-1 signaling to upregulate complement receptor 3 (CR3) in neutrophils and increase their phagocytic activity (13,14), as well as to increase the Dectin-1-induced activation of Mac-1, a component of CR3 (20). IL-33-induced CR3 activation also results in the production of high levels of reactive oxygen species and fungicidal activity in neutrophils.…”

The characteristics of vessel lining cells in normal spleens and their role in the pathobiology of myelofibrosis

“…IL-33, in particular, has been considered to play a possible role in myeloproliferative neoplasm biogenesis. 46,47 The circulation level of IL-15 has also been reported to be increased in the patients with MF. 32 An MF SVEC cell line promoted the generation of greater numbers of hematopoietic progenitor cells from normal splenic CD34…”

Cytokine regulation of stem cells

“…Other than targeting various immune cells during inflammation, IL-33 also targets hematopoietic stem and progenitor cells to promote myelopoiesis and myeloid cell migration [20].…”