STING controls intestinal homeostasis through promoting antimicrobial peptide expression in epithelial cells.

Abstract

Stimulator of interferon genes (STING) has been shown to play a critical role in orchestrating immune responses to various pathogens through sensing cyclic dinucleotides. However, how STING regulates intestinal homeostasis is still not completely understood. In this study, we found that STING-/- mice were more susceptible to enteric infection with Citrobacter rodentium compared to wild-type (WT) mice evidenced by more severe intestinal inflammation and impaired bacterial clearance. STING-/- mice demonstrated lower expression of REG3γ but not β-defensins and Cramp in IECs. Consistently, STING-/- IECs showed reduced capacity to inhibit bacterial growth. STING agonists, both 10-carboxymethyl-9-acridanone (CMA) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), promoted REG3γ expression IECs. Furthermore, STING agonists promoted WT but not REG3γ-deficient IEC bacterial killing. Mechanistically, STING agonists activated STAT3 and promoted glycolysis in IECs. Inhibition of STAT3 pathway and glycolysis suppressed STING-induced REG3γ production in IECs, and abrogated STING-mediated IEC killing of C. rodentium. Additionally, treatment with the STING ligand, 2,3-cGAMP, inhibited C. rodentium-induced colitis in vivo. Overall, STING promotes IEC REG3γ expression to inhibit enteric infection and intestinal inflammation, thus, maintaining the intestinal homeostasis.

• Authors: Yanbo Yu, Wenjing Yang, Anthony J Bilotta, Yu Yu, Xiaojing Zhao, Zheng Zhou, Suxia Yao, Jimin Xu, Jia Zhou, Sara M Dann, Yanqing Li, Yingzi Cong
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 11 Pg. 15417-15430 (11 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 32969062 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Federation of American Societies for Experimental Biology.

Chemical References

• Membrane Proteins
• Pancreatitis-Associated Proteins
• Pore Forming Cytotoxic Proteins
• Reg3g protein, mouse
• Sting1 protein, mouse

Topics

• Animals
• Citrobacter rodentium (drug effects, growth & development)
• Colitis (drug therapy, etiology, pathology)
• Enterobacteriaceae Infections (complications, immunology, microbiology, pathology)
• Epithelial Cells (drug effects, immunology, metabolism, pathology)
• Homeostasis
• Immunity, Innate
• Inflammation (drug therapy, etiology, pathology)
• Intestinal Mucosa (drug effects, immunology, metabolism, pathology)
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pancreatitis-Associated Proteins (genetics, metabolism)
• Pore Forming Cytotoxic Proteins (pharmacology)