Epithelial regeneration is modulated by chitin and chitinase activity
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 health and regeneration after epithelial injury.  In mice, damage to epithelial cells results in loss of homeostatic lung chitinase activity and accumulation of environmental chitin substrates; these disturbances 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, demonstrating that chitin degradation is crucial for restoring lung homeostasis after perturbation.  The ILC2-chitinase response circuit thus comprises a tissue adaptation to a widespread environmental constituent and may be a target for alleviating persistent post-injury lung epithelial and immune dysfunction. Overall design: To investigate whether influenza virus infection in WT and AMCase deficient epithelial cells alters differentiation and proliferation program, mice were intransally inoculated with PFU 250 of H1N1/PR8 strain of influenza virus intranasally under isoflurane anesthesia prior to sacrifice 14 days post infection for isolation and analysis of progenitor-like epithelial cells through RNA sequencing.