Functional interleukin‐33 receptors are expressed in early progenitor stages of allergy‐related granulocytes

Abstract

SummaryInterleukin-33 (IL-33) induces T helper type 2 (Th2) cytokine production and eosinophilia independently of acquired immunity, leading to innate immunity-mediated allergic inflammation. Allergy-related innate myeloid cells such as eosinophils, basophils and mast cells express the IL-33 receptor (IL-33R), but it is still unknown how IL-33 regulates allergic inflammation involving these cells and their progenitors. Here, we revealed that the functional IL-33R was expressed on eosinophil progenitors (EoPs), basophil progenitors (BaPs) and mast cell progenitors (MCPs). In the presence of IL-33, these progenitors did not expand, but produced a high amount of Th2 and pro-inflammatory cytokines such as IL-9, IL-13, IL-1b and IL-6. The amount of cytokines produced by these progenitors was greater than that by mature cells. In vivo, IL-33 stimulated the expansion of EoPs, but it was dependent upon the elevated serum IL-5 that is presumably derived from type 2 innate lymphoid cells that express functional IL-33R. These data collectively suggest that EoPs, BaPs and MCPs are not only the sources of allergy-related granulocytes, but can also be sources of allergy-related cytokines in IL-33-induced inflammation. Because such progenitors can differentiate into mature granulocytes at the site of inflammation, they are potential therapeutic targets in IL-33-related allergic diseases.

Bone marrow type 2 innate lymphoid cells: a local source of interleukin‐5 in interleukin‐33‐driven eosinophilia

“…d), however, in PBS‐treated control mice, representing homeostatic conditions, anti‐IL‐5 treatment led to a significant decrease of circulating eosinophils, as previously shown . Indeed, consistent with our results, two recent studies reported elevated IL‐5 in the serum of IL‐33‐treated mice and where IL‐33‐induced eosinophilia was impaired upon neutralization of IL‐5 . However, interestingly, we also found that the expression of eotaxin‐2/CCL24 in serum (Fig.…”

“…acquired IL5R α expression), suggesting a fine‐tuned interplay between IL‐33 and IL‐5 in hematopoietic differentiation, which has been described in further detail by others . In a recent study, ST2 expression in mature granulocytes including eosinophils, basophils and mast cells, was compared with the expression of the ST2 receptor in precursor cells . Eosinophil progenitors, basophil progenitors and mast cell progenitors were all found to express ST2 at higher levels than the mature cells.…”

“…Eosinophil progenitors, basophil progenitors and mast cell progenitors were all found to express ST2 at higher levels than the mature cells. The functional relevance of this observation was documented by increased IL‐33‐induced cytokine production in vitro (IL‐1β, IL‐6, IL‐9 and IL‐13) by the progenitors compared with the mature granulocytes . Importantly, functional implications of ST2 expression on CD34 + progenitors have previously been reported in humans where CD34 + ST2 + cells in peripheral blood were found to produce IL‐5 in response to IL‐33 stimulation .…”

“…Similarly, eotaxin‐1/CCL11 and eotaxin‐2/CCL24, ligands for the cell surface CC‐chemokine receptor 3 (CCR3), regulate eosinophil homing to tissues both in cooperation with IL‐5 and through IL‐5‐independent pathways . IL‐5 is typically considered a product of type 2 polarized T helper (Th) cells, however, eosinophils and their progenitor cells also produce a wide range of cytokines that influence hematopoietic differentiation, including IL‐5 . IL‐5 is also produced by other innate immune cells, and during the last decade, type 2 innate lymphoid cells (ILC2s) have emerged as a new important source of type 2 cytokines in response to IL‐33 .…”

Human eosinophils and mast cells: Birds of a feather flock together

“…IL‐33 promotes eosinophil‐mediated inflammation and our lab has recently demonstrated that Siglec‐8 engagement on IL‐33‐primed eosinophils results in apoptosis . Lately it has been shown that eosinophil progenitors express a functional IL‐33 receptor capable of producing pro‐inflammatory cytokines at levels that far surpass those observed in mature eosinophils …”