Autophagy and endoplasmic reticulum stress coordinate protective interleukin-22 signals in the intestinal epithelium.

Tran, Florian ORCID

Inflammatory bowel diseases (IBD) are playing a more and more important socioeconomic role due to increasing incidences. However, the detailed pathophysiology is not fully understood, yet. This is reflected by the yet unsatisfactory treatment efficiency of even the most modern drugs under development. Genetic factors, environmental triggers, lifestyle and microbial signals are interactively contributing to the development of IBD. Coding variants of the IBD risk genes ATG16L1 and XBP1 have been associated with defective autophagy, deregulation of endoplasmic reticulum (ER) function and impaired pathogen clearance. IL-22 is a barrier protective cytokine by inducing regeneration and antimicrobial responses in the intestinal mucosa. Here, we show that XBP1 and ATG16L1 critically orchestrates beneficial IL-22 signalling in intestinal epithelium. IL-22 stimulation physiologically leads to transient ER stress, intracellular release of dsDNA and subsequent activation of the cGAS-STING pathway. Loss of ATG16L1 exacerbates IL-22-induced ER stress and augments STING-dependent IFN-I responses in IECs. IFN-I amplifies epithelial TNFα production downstream of IL-22 and leads to necroptotic cell death. In vivo, IL-22 treatment in Atg16l1ΔIEC mono- and Atg16l1ΔIEC/Xbp1ΔIEC double knockout mice potentiates endogenous ileal inflammation and causes widespread necroptotic epithelial cell death, which can be partially rescued by neutralising the IFN-I signalling using anti-IFNAR antibodies. Under conditions of chronic intestinal inflammation and with clear genetic “hits” to the autophagic and ER stress machinery like in human IBD, however, such a fate of IL-22 signals may crucially contribute to a vicious circle of tissue damage and inflammation.

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Tran, Florian: Autophagy and endoplasmic reticulum stress coordinate protective interleukin-22 signals in the intestinal epithelium.. 2019.

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