Abstract
Abstract Polymorphisms of the autophagy-related gene ATG16L1 are known to contribute to the genetic risk for developing Crohn’s Disease (CD), an inflammatory bowel disease that can affect the entire gastrointestinal tract. Previous studies have shown a role for autophagy in the intestinal epithelium both in Paneth cell function and in protection from intestinal damage, but no spontaneous disease at baseline. Here, we challenged mice specifically deleted for Atg16l1 in intestinal epithelial cells (Atg16l1ΔIEC) with the anti-CD3 mediated model of acute small intestinal injury. Rapid T cell activation by anti-CD3 injection results in small intestinal damage within 24 hours of injection, this typically self-resolves in wild-type mice 5 days post treatment. We found that autophagy sufficiency was protective in anti-CD3 induced injury. Atg16l1ΔIEC mice had higher mortality and worsened pathology in comparison to their wild-type littermates. We found indications of increased intestinal barrier permeability and crypt cell apoptosis in Atg16l1ΔIEC mice. In addition, expression of interferon gamma (IFNγ) and tumour necrosis factor (TNF) was significantly increased in Atg16l1ΔIEC mice, cytokines that have been implicated in driving intestinal injury in autophagy-deficient mice. Antibody-mediated blockade of either TNF or IFNγ rescued survival of Atg16l1ΔIEC mice. Interestingly, anti-IFNγ abolished both the crypt cell apoptosis and Paneth cell death at 24 hours, whereas anti-TNF did not decrease the crypt cell apoptosis or Paneth cell death, suggesting IFNγ is the primary contributor to pathology in this model. Overall, this work implicates intestinal epithelial autophagy in the protective response to acute intestinal injury.
Published Version
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