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STING controls intestinal homeostasis through promoting antimicrobial peptide expression in epithelial cells
Author(s) -
Yu Yanbo,
Yang Wenjing,
Bilotta Anthony J.,
Yu Yu,
Zhao Xiaojing,
Zhou Zheng,
Yao Suxia,
Xu Jimin,
Zhou Jia,
Dann Sara M.,
Li Yanqing,
Cong Yingzi
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202001524r
Subject(s) - sting , stimulator of interferon genes , inflammation , immune system , homeostasis , biology , chemistry , microbiology and biotechnology , immunology , innate immune system , engineering , aerospace engineering
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.