2. Academic Validation
  3. mtDNA-STING pathway promotes necroptosis-dependent enterocyte injury in intestinal ischemia reperfusion

mtDNA-STING pathway promotes necroptosis-dependent enterocyte injury in intestinal ischemia reperfusion

  • Cell Death Dis. 2020 Dec 11;11(12):1050. doi: 10.1038/s41419-020-03239-6.
Xufei Zhang 1,  Jie Wu 1 2,  Qinjie Liu 3,  Xuanheng Li 1,  Sicheng Li 3,  Jun Chen 1 3,  Zhiwu Hong 1 3,  Xiuwen Wu 4 5,  Yun Zhao 6,  Jianan Ren 7 8
Affiliations

Affiliations

  • 1 Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, PR China.
  • 2 Research Center of Surgery, BenQ Medical Center, the Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210021, PR China.
  • 3 Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China.
  • 4 Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, PR China. lygwxw@163.com.
  • 5 Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China. lygwxw@163.com.
  • 6 Research Center of Surgery, BenQ Medical Center, the Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210021, PR China. zhaoyun0562019@163.com.
  • 7 Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, 210002, PR China. jiananr@gmail.com.
  • 8 Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, PR China. jiananr@gmail.com.
PMID: 33311495 DOI: 10.1038/s41419-020-03239-6
Abstract

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. We found that circulating RIPK3 was significantly increased and had a positive correlation with markers of enterocyte injury in critically ill patients with intestinal injury. Moreover, the levels of circulating mtDNA were also associated with the levels of circulating RIPK3. To explore the relationship between mtDNA and intestinal Necroptosis, mice were treated with the intraperitoneal injection of mtDNA, and Necroptosis signaling was remarkably activated and the inhibition of Necroptosis alleviated mtDNA-induced intestinal injury. Furthermore, STING knockout mice showed an alleviated intestinal Necroptosis. In intestinal I/R injury, mtDNA was released from IECs 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. Our results indicated that mtDNA-STING signaling can contribute to intestinal I/R injury by promoting IEC Necroptosis. STING-mediated both IFN and TNF-α signaling can trigger intestinal nercroptosis.

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