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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)15417-15430
Number of pages14
JournalFASEB Journal
Volume34
Issue number11
DOIs
StatePublished - Nov 1 2020

Keywords

  • IEC
  • REG3γ
  • STING
  • intestinal homeostasis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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