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- W2768916343 abstract "The airway epithelium forms the primary defense against inhaled allergens and environmental insults to the respiratory system. Aside from acting as a physical barrier, the epithelium also signals for reparative and inflammatory responses by generating various epithelial-derived cytokines and mediators. Chief among these is the epithelial secretion of the alarmin cytokine IL-33, which in turn induces type 2 immune responses. Although these processes serve a protective mechanism by promoting epithelial regenerative pathways, chronic activation of such type 2 responses contribute to chronic respiratory diseases such as asthma and COPD. We recently demonstrated that epithelial IL-33 secretion in response to various injurious triggers is dependent on H2O2 production by the NADPH oxidase dual oxidase 1 (DUOX1), and that this was associated with activation and oxidation of the non-receptor tyrosine kinase Src. However, the precise role of Src in these responses is still unclear, and we hypothesized that redox-dependent activation of Src is critical for increased IL-33 secretion and downstream type 2 responses to allergens. Pretreatment of mice with the Src family kinase inhibitor AZD0530 was found to significantly attenuate epithelial Src activation, as well as expression and secretion of IL-33 and the downstream type 2 cytokines IL-5 and IL-13, in response to acute challenge with house dust mite (HDM). Similar findings were obtained using isolated mouse tracheal epithelial cells (MTEC), in which siRNA-dependent silencing of Src resulted in diminished HDM-induced production of IL-33, as well as IL-5 and IL-13. Interestingly, we noted that HDM-induced IL-33 secretion is diminished upon blockade of the IL-33 receptor ST2, suggesting that IL-33 regulates its own secretion through a positive feedback mechanism. Indeed, induction of type 2 cytokine secretion (IL-13) in airway epithelial cells by direct stimulation with IL-33 was found to be DUOX1-dependent, and associated with increased H2O2 production and activation/oxidation of Src. Building on our recent findings that DUOX1-dependent activation of Src involves oxidation of its C185 and C277 residues, preliminary studies using H292 lung epithelial cells transfected with C185A or C277A Src variants indicate that expression of these variants leads to suppressed HDM-induced IL-33 secretion. Overall, our studies identify Src as a critical mediator of allergen-induced IL-33 secretion and innate type 2 immune responses, and highlight the importance of various redox-sensitive Cys residues in these responses." @default.
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- W2768916343 date "2017-11-01" @default.
- W2768916343 modified "2023-09-27" @default.
- W2768916343 title "Airway Epithelial IL-33 Secretion and Feedback Signaling is Associated with Redox Activation of Src Kinase" @default.
- W2768916343 doi "https://doi.org/10.1016/j.freeradbiomed.2017.10.319" @default.
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