IRE1α Regulation of Airway Epithelial Fate and Mucus Metaplasia

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Abstract In the airway, epithelial cells can transiently differentiate into goblet cells, but dysregulated immune responses to allergen lead to persistent goblet cell metaplasia and mucus hypersecretion in rhinosinusitis and severe asthma. The molecular mechanisms that govern goblet cell differentiation are incompletely understood, and no available therapy directly targets this process to alleviate mucus-related symptoms. Here, we show that the unfolded protein response (UPR) and its most deeply-conserved mediator, IRE1α, are activated as human basal cells differentiate into highly secretory goblet cells. Conditional knockout of IRE1α in the mouse lung epithelium demonstrates that IRE1α is cell autonomously required for efficient goblet cell metaplasia stimulated by Th2 inflammation in allergen-challenged mice. Likewise, IRE1α loss of function by genetic knockout or a highly selective kinase inhibitor of IRE1α (KIRA8) blocks goblet cell metaplasia airway epithelial cells cultured at air-liquid interface (ALI). To further delineate the molecular mechanism of IRE1α's regulation goblet cell metaplasia, we cultured cells at ALI with a kinase modulator (PAIR2) that blocks IRE1α's RIDD activity while preserving its XBP1 splicing activity. We find that IRE1α's XBP1 splicing activity regulates the fate of differentiating airway epithelial cells, in contrast to the alveolus, where IRE1α's RIDD activity controls plasticity. In cells from human donors, the kinase inhibitor KIRA8 blocks IL-13 induced goblet cell differentiation, suggesting that kinase inhibitors of IRE1α may have therapeutic potential for controlling symptoms of mucus hypersecretion in asthma patients. Ongoing work will further define the transcriptional targets of XBP1 in differentiating airway cells, and a possible role for IRE1α in suppressing ciliogenesis. Our data suggests that IRE1α may enhances goblet cell metaplasia by simultaneously promoting secretory maturation through XBP1 and possibly suppressing ciliary fate through RIDD. Grant Support AADCRC IOF Fund (NIAID)U19AI077439 (NIAID)K08HL157654 (NHLBI)F32HL145990 (NHLBI)T32HL007185 (NHLBI)

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