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

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 withCitrobacter rodentiumcompared to wild-type (WT) mice evidenced by more severe intestinal inflammation and impaired bacterial clearance. STING(-/-)mice demonstrated lower expression of REG3 gamma but not beta-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 REG3 gamma expression IECs. Furthermore, STING agonists promoted WT but not REG3 gamma-deficient IEC bacterial killing. Mechanistically, STING agonists activated STAT3 and promoted glycolysis in IECs. Inhibition of STAT3 pathway and glycolysis suppressed STING-induced REG3 gamma production in IECs, and abrogated STING-mediated IEC killing ofC. rodentium. Additionally, treatment with the STING ligand, 2,3-cGAMP, inhibitedC. rodentium-induced colitis in vivo. Overall, STING promotes IEC REG3 gamma expression to inhibit enteric infection and intestinal inflammation, thus, maintaining the intestinal homeostasis.u