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

Area of Science:

• Gastroenterology
• Immunology
• Cell Biology

Background:

• Crohn disease (CD) progression involves intestinal barrier dysfunction.
• Genetic variants in ATG16L1 increase CD risk and impact intestinal epithelial cells.
• Autophagy plays a critical role in maintaining intestinal homeostasis.

Purpose of the Study:

• To investigate the role of Atg16l1 in intestinal epithelial cells (IECs) during T-cell-mediated enteropathy.
• To determine the impact of Atg16l1 deficiency on epithelial damage, inflammation, and recovery.
• To elucidate the signaling pathways driving pathology in Atg16l1-deficient IECs.

Main Methods:

• Utilized a murine model of anti-CD3-induced enteropathy.
• Generated mice with specific deletion of Atg16l1 in IECs (Atg16l1^ΔIEC).
• Administered blocking antibodies against tumor necrosis factor (TNF) and interferon-gamma (IFN-γ).

Main Results:

• Atg16l1^ΔIEC mice exhibited increased intestinal damage, crypt cell death, inflammation, and reduced survival.
• Atg16l1 deficiency impaired epithelial recovery and IEC proliferation.
• Pathology was primarily driven by IFN-γ signaling; anti-IFN-γ treatment abrogated IEC death.

Conclusions:

• Atg16l1 deficiency exacerbates intestinal injury in a T-cell-mediated enteropathy model.
• IFN-γ signaling is a key driver of IEC death in this context.
• Targeting IFN-γ may be a therapeutic strategy for CD patients with ATG16L1 variants.