TY - JOUR
T1 - STING controls intestinal homeostasis through promoting antimicrobial peptide expression in epithelial cells
AU - Yu, Yanbo
AU - Yang, Wenjing
AU - Bilotta, Anthony J.
AU - Yu, Yu
AU - Zhao, Xiaojing
AU - Zhou, Zheng
AU - Yao, Suxia
AU - Xu, Jimin
AU - Zhou, Jia
AU - Dann, Sara M.
AU - Li, Yanqing
AU - Cong, Yingzi
N1 - Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - IEC
KW - REG3γ
KW - STING
KW - intestinal homeostasis
UR - http://www.scopus.com/inward/record.url?scp=85091386769&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091386769&partnerID=8YFLogxK
U2 - 10.1096/fj.202001524R
DO - 10.1096/fj.202001524R
M3 - Article
C2 - 32969062
AN - SCOPUS:85091386769
SN - 0892-6638
VL - 34
SP - 15417
EP - 15430
JO - FASEB Journal
JF - FASEB Journal
IS - 11
ER -