Abstract
Over the last decade, significant interest in the contribution of three “epithelial-derived cytokines,” such as thymic stromal lymphopoietin, interleukin 25, and interleukin 33 (IL-33), has developed. These cytokines have been strongly linked to the early events that occur during allergen exposures and how they contribute to the subsequent type 2 immune response. Of these three cytokines, IL-33 has proven particularly interesting because of the strong associations found between both it and its receptor, ST2, in several genome-wide association studies of allergic diseases. Further work has demonstrated clear mechanisms through which this cytokine might orchestrate allergic inflammation, including activation of several key effector cells that possess high ST2 levels, including mast cells, basophils, innate lymphoid cells, and eosinophils. Despite this, controversies surrounding IL-33 seem to suggest the biology of this cytokine might not be as simple as current dogmas suggest including: the relevant cellular sources of IL-33, with significant evidence for inducible expression in some hematopoietic cells; the mechanistic contributions of nuclear localization vs secretion; secretion and processing mechanisms; and the biological consequences of IL-33 exposure on different cell types. In this review, we will address the evidence for IL-33 and ST2 regulation over eosinophils and how this may contribute to allergic diseases. In particular, we focus on the accumulating evidence for a role of IL-33 in regulating hematopoiesis and how this relates to eosinophils as well as how this may provide new concepts for how the progression of allergy is regulated.
Highlights
Allergic diseases are increasing worldwide, and the mechanisms of both allergic sensitization and the subsequent effector responses following reexposure, including by eosinophils, are still not fully understood
Allergens interact with mucosal tissue surfaces in many ways including through toll-like receptors 2 and 4 (TLR2 and TLR4), dectin-1, and protease-activated receptor-2 (PAR-2) [22], wherein dectin-1 and PAR-2 are necessary for allergen-induced increases in interleukin 33 (IL-33) in lung tissues [23, 24]
We identified an eosinophil precursors (EoPres) that is eosin negative and exhibits the characteristic donut-shaped nuclei, which is driven by IL-33 exposure [44] (Figure 1A)
Summary
Allergic diseases are increasing worldwide, and the mechanisms of both allergic sensitization and the subsequent effector responses following reexposure, including by eosinophils, are still not fully understood. Allergens interact with mucosal tissue surfaces in many ways including through toll-like receptors 2 and 4 (TLR2 and TLR4), dectin-1, and protease-activated receptor-2 (PAR-2) [22], wherein dectin-1 and PAR-2 are necessary for allergen-induced increases in IL-33 in lung tissues [23, 24] The source of such increases in IL-33 remains poorly defined: while several studies have described IL-33 secretion from structural cells [17, 25,26,27], mast cells [28], DCs [9], and human monocytes [29] can express and release IL-33. Both EoP and EoPre are IL-5Rα+, but EoPre is Siglec-FloSSClo whereas EoP is Siglec-F+SSChi
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