p53 suppresses MHC class II presentation by intestinal epithelium to protect against radiation-induced gastrointestinal syndrome

Jianming Wang, Chun-Yuan Chang, Xue Yang, Fan Zhou, Juan Liu, Jill Bargonetti, Lanjing Zhang, Ping Xie, Zhaohui Feng () and Wenwei Hu ()
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Jianming Wang: Rutgers University
Chun-Yuan Chang: Rutgers University
Xue Yang: Rutgers University
Fan Zhou: Rutgers University
Juan Liu: Rutgers University
Jill Bargonetti: Hunter College, City University of New York
Lanjing Zhang: Rutgers University
Ping Xie: Rutgers University
Zhaohui Feng: Rutgers University
Wenwei Hu: Rutgers University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Radiation-induced gastrointestinal syndrome is a major complication and limiting factor for radiotherapy. Tumor suppressor p53 has a protective role in radiation-induced gastrointestinal toxicity. However, its underlying mechanism remains unclear. Here we report that regulating the IL12-p40/MHC class II signaling pathway is a critical mechanism by which p53 protects against radiation-induced gastrointestinal syndrome. p53 inhibits the expression of inflammatory cytokine IL12-p40, which in turn suppresses the expression of MHC class II on intestinal epithelial cells to suppress T cell activation and inflammation post-irradiation that causes intestinal stem cell damage. Anti-IL12-p40 neutralizing antibody inhibits inflammation and rescues the defects in intestinal epithelial regeneration post-irradiation in p53-deficient mice and prolongs mouse survival. These results uncover that the IL12-p40/MHC class II signaling mediates the essential role of p53 in ensuring intestinal stem cell function and proper immune reaction in response to radiation to protect mucosal epithelium, and suggest a potential therapeutic strategy to protect against radiation-induced gastrointestinal syndrome.

Date: 2024
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DOI: 10.1038/s41467-023-44390-w

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