An ILC2-chitinase circuit restores lung homeostasis after epithelial injury 2045

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Abstract Description Epithelial injury underlies fibrotic and inflammatory lung diseases during which regenerative responses become dysregulated or recurrently engaged. Although environmental exposures are risk factors for severe lung disease, specific drivers of persistent epithelial and immune dysfunction are poorly understood. Here we identify a feedback circuit triggered by chitin, a common component of airborne particulate matter, that impacts lung regeneration after epithelial injury. Damage to epithelial cells results in loss of homeostatic lung chitinase activity and corresponding accumulation of environmental chitin substrates, which impair epithelial renewal and drive activation of group 2 innate lymphoid cells (ILC2s). ILC2s, in turn, restore chitinase activity by inducing acidic mammalian chitinase (AMCase) in regenerating epithelial cells, thereby promoting chitin degradation, epithelial differentiation, and inflammatory resolution. Mice lacking AMCase or ILC2s fail to clear airway chitin and exhibit exacerbated inflammation, impaired epithelial regeneration, and increased mortality following epithelial injury. These effects are ameliorated by chitinase replacement therapy or AMCase overexpression, suggesting that chitin degradation is crucial for restoring lung homeostasis. The ILC2-chitinase response circuit thus comprises a tissue adaptation to environmental constituents and may be a target for alleviating persistent post-injury lung epithelial and immune dysfunction. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

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