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ATG16L1 protects from interferon-γ-induced cell death in the small intestinal crypt. | LitMetric

ATG16L1 protects from interferon-γ-induced cell death in the small intestinal crypt.

Mucosal Immunol

Department of Immunology, University of Toronto, Toronto, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. Electronic address:

Published: April 2023

AI Article Synopsis

  • * Researchers deleted Atg16l1 from intestinal epithelial cells in mice, which resulted in increased intestinal damage, inflammation, and poor recovery, highlighting the gene's protective role.
  • * Findings indicate that interferon (IFN)-γ is a key factor in driving pathology in the absence of Atg16l1, suggesting that therapies targeting IFN-γ might benefit CD patients with ATG16L1 genetic variants.

Article Abstract

The breakdown of the intestinal mucosal barrier is thought to underlie the progression to Crohn disease (CD), whereby numerous risk factors contribute. For example, a genetic polymorphism of the autophagy gene ATG16L1, associated with an increased risk of developing CD, contributes to the perturbation of the intestinal epithelium. We examined the role of Atg16l1 in protecting the murine small intestinal epithelium from T-cell-mediated damage using the anti-CD3 model of enteropathy. Our work showed that mice specifically deleted for Atg16l1 in intestinal epithelial cells (IECs) (Atg16l1) had exacerbated intestinal damage, characterized by crypt epithelial cell death, heightened inflammation, and decreased survival. Moreover, Atg16l1 deficiency delayed the recovery of the intestinal epithelium, and Atg16l1-deficient IECs were impaired in their proliferative response. Pathology was largely driven by interferon (IFN)-γ signaling in Atg16l1 mice. Mechanistically, although survival was rescued by blocking tumor necrosis factor or IFN-γ independently, only anti-IFN-γ treatment abrogated IEC death in Atg16l1 mice, thereby decoupling IEC death and survival. In summary, our findings suggest differential roles for IFN-γ and tumor necrosis factor in acute enteropathy and IEC death in the context of autophagy deficiency and suggest that IFN-γ-targeted therapy may be appropriate for patients with CD with variants in ATG16L1.

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Source
http://dx.doi.org/10.1016/j.mucimm.2023.02.001DOI Listing

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