STING controls intestinal homeostasis through promoting antimicrobial peptide expression in epithelial cells.
STING controls intestinal homeostasis through promoting antimicrobial peptide expression in epithelial cells.
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DOI：
10.1096/fj.202001524r
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Cong Y
中科院分区：
文献类型：
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作者：
Yu Y;Yang W;Bilotta AJ;Yu Y;Zhao X;Zhou Z;Yao S;Xu J;Zhou J;Dann SM;Li Y;Cong Y
干扰素基因刺激因子（STING）通过检测环状二核苷酸在免疫应答中发挥重要作用。然而，STING如何调节肠道内稳态仍然没有完全了解。在这项研究中，我们发现STING−/−小鼠比WT小鼠更容易感染啮齿类柠檬酸杆菌，表现为更严重的肠道炎症和细菌清除受损。STING−/−小鼠在IEC中表现出REG 3 γ的表达较低，但β-防御素和Cramp的表达不低。一致地，STING−/− IEC显示抑制细菌生长的能力降低。STING激动剂10-羧甲基-9-吖啶酮（CMA）和5，6-二甲基咕吨酮-4-乙酸（DMXAA）均促进IEC的REG 3 γ表达。此外，STING激动剂促进WT但不促进REG 3 γ缺陷型IEC细菌杀伤。从机制上讲，STING激动剂激活STAT 3并促进IEC中的糖酵解。抑制STAT 3途径和糖酵解抑制了STING诱导的IEC中REG 3 γ的产生，并消除了STING介导的IEC对啮齿类柠檬酸杆菌的杀伤。此外，用STING配体2，3-cGAMP处理在体内抑制Citrobactor rodentium诱导的结肠炎。总体而言，STING促进IEC REG 3 γ表达以抑制肠道感染和肠道炎症，从而维持肠道稳态。
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 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 Citrobactor rodentium. Additionally, treatment with the STING ligand, 2,3-cGAMP, inhibited Citrobactor rodentium-induced colitis in vivo. Overall, STING promotes IEC REG3γ expression to inhibit enteric infection and intestinal inflammation, thus, maintaining the intestinal homeostasis.