GSDMD protects intestinal epithelial cells against bacterial infections through its N-terminal activity affecting intestinal immune homeostasis

Abstract

The intestinal mucosal barrier serves as a vital guardian of the gut health, maintaining a delicate equilibrium between gut microbiota and host immune homeostasis. Gasdermin D (GSDMD), a key executioner of pyroptosis downstream of the inflammasome, has been found to play intricate roles in modulating colitis by influencing intestinal macrophages and regulating mucus secretion from goblet cells. However, the exact nature of the regulatory function of GSDMD in maintaining intestinal immune homeostasis and defending against pathogens remains to be elucidated. In the current study, by using the Citrobacter rodentium infection model, we found that GSDMD played a key role in the defense against intestinal Citrobacter rodentium infection, with high expression levels in intestinal epithelial and lamina propria myeloid cells. Our results showed that GSDMD acted specifically in intestinal epithelial cells to combat the infection, independently of its effects on antimicrobial peptides or mucin secretion. Instead, the resistance was mediated by the N-terminal fragment of GSDMD, highlighting its importance in intestinal immunity. However, the specific mechanism underlying the N-terminal activity of GSDMD in protecting against intestinal bacterial infections requires future investigation.

Keywords

GSDMD / pyroptosis / Citrobacter rodentium infection / intestinal mucosal barrier

Fundings

This work was supported by the National Key Research and Development Program of China (Grant No. 2022YFA1303900 to S.Y.), the National Natural Science Foundation of China (Grant Nos. 32270921 and 82070567 to S.Y. and 82204354 to Y.H.), the Open Project of the State Key Laboratory of Reproductive Medicine of Nanjing Medical University (Grant No. SKLRM-2021B3 to S.Y.), the Talent Cultivation Project of "Organized Scientific Research" of Nanjing Medical University (Grant No. NJMURC20220014 to S.Y.), the Natural Science Foundation of Jiangsu Province (Grant No. BK20221352 to B.W.), the Jiangsu Provincial Outstanding Postdoctoral Program (Grant No. 2022ZB419 to Y.H.), the Postdoctoral Research Funding Project of Gusu School (Grant No. GSBSHKY202104 to Y.H.), and the China Postdoctoral Science Foundation (Grant No. 2023T160329 to Y.H.).

Acknowledgments

None.

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