| Summary: | Atopic asthma is a chronic inflammatory disease of the lungs that is generally marked by excessive Th2 inflammation against a variety of structurally and functionally distinct allergens. Our studies demonstrated that two distinct Th2 stimuli, immune complexes (ICs) and house dust mite (HDM), both utilized FcRgamma-associated receptors, FcgammaRIII and Dectin-2 respectively, on antigen presenting cells (APCs) to promote Th2-mediated lung inflammation. We sought to identify downstream targets of FcRgamma signaling that could contribute to this process and demonstrated that both ICs and HDM induced expression in monocytes and dendritic cells (DCs) of IL-33, a critical mediator in asthma pathogenesis. Upregulation of IL-33 in DCs was dependent on FcRgamma, toll-like receptor 4 (TLR4), and phosphoinositide 3 (PI3)-kinase. Reconstitution of Th2-type responses in the lungs occurred when stimulated wildtype (WT) bone marrow derived DCs (BMDCs) were adoptively transferred into either IL-33 -/- or FcRgamma-/- mice. Further investigations into the role of IL-33 from APCs during Th2-mediated inflammation suggested that IL-33 may be acting in a cell intrinsic manner to regulate monocyte extravasation from the vasculature to the interstitium. Intravascular staining of APCs revealed that compared to WT mice, monocytes in IL-33-/- mice and FcgammaRIII -/- mice were able to take up antigen but failed to accumulate in the interstitium. Overall, these findings identified a common pathway that can be utilized by allergens to promote development of DCs that will skew towards a Th2 phenotype (DCTh2), but how IL-33 from APCs regulates Th2-type responses remains an area of ongoing investigation.
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