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

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          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.

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          Author and article information

          Journal
          FASEB J
          FASEB journal : official publication of the Federation of American Societies for Experimental Biology
          Wiley
          1530-6860
          0892-6638
          Nov 2020
          : 34
          : 11
          Affiliations
          [1 ] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
          [2 ] Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, P.R. China.
          [3 ] Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
          [4 ] Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
          [5 ] Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
          Article
          NIHMS1631568
          10.1096/fj.202001524R
          7606834
          32969062
          dcc7c158-0ed6-4df0-8adf-1559b671f2d0

          IEC, intestinal homeostasis, STING, REG3γ

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