MtDNA-STING Pathway Promotes Necroptosis-Dependent Enterocyte Injury in Intestinal Ischemia Reperfusion

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Background: Intestinal ischemia reperfusion (I/R) injury is the important pathogenesis for acute intestinal barrier disruption. The STING signaling is associated with gut homeostasis and barrier integrity. However, the biological function and regulation of STING signaling in intestinal I/R injury are not yet fully understood. As the ligand of STING signaling, the mitochondrial DNA (mtDNA) has been found to be associated with necroptosis. It still remains unknown whether mtDNA-STING signaling triggers intestinal necroptosis in intestinal I/R injury. Methods: The levels of circulating receptor interacting protein kinase 3 (RIPK3) were first collected to explore the role of necroptosis in critically ill patients with intestinal injury. Furthermore, the relationship between mtDNA-STING signaling and necroptosis was explored through establishing a murine model of intestinal I/R injury in wild-type mice and STING knockout mice. Primary intestinal epithelial cells (IECs) were isolated to investigate downstream signaling of STING leading to intestinal necroptosis. Findings: In critically ill patients with intestinal injury, circulating RIPK3 was significantly increased and had a positive correlation with markers of enterocyte injury. Moreover, the levels of circulating mtDNA were also associated with the levels of circulating RIPK3. After the intraperitoneal injection of mtDNA in mice, necroptosis signaling was remarkably activated and the inhibition of necroptosis alleviated mtDNA-induced intestinal injury. Furthermore, STING knockout mice showed an alleviated necroptosis. In intestinal I/R injury, mtDNA released from IECs was released and necroptosis was also triggered, companied with a significant decrease of RIPK3 in the intestine. STING knockout mice markedly attenuated intestinal necroptosis and intestinal I/R injury. Finally, we found that mtDNA-mediated STING signaling triggered necroptosis through synergistic IFN and TNF-α signaling in primary IECs. Interpretation: Our results indicated that mtDNA-STING signaling can contribute to intestinal I/R injury by promoting IEC neroptosis. STING-mediated both IFN and TNF-α signaling can trigger intestinal nercroptosis. Funding Statement: This work was supported by the National Natural Science Foundation of China (81801971, 81772052), Distinguished Scholars Foundation of Jiangsu Province (JCRCB2016006). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The collection of human blood samples was approved by the Institutional Review Board Ethics Committee at Jinling Hospital. Before collecting blood samples, all patients and healthy adult volunteers provided written informed consent. The care and use of the animals were approved by Jinling Hospital Animal Care Committee.