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

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.

Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury

“…Specifically, numerous clinical studies have confirmed that the level of circulating mitochondrial DNA (mtDNA) is closely related to the severity and prognosis of sepsis and ARDS [ 2 ]. In our previous studies, we have found that mtDNA plays a fundamental role in the mechanism of cellular injury and lethal sepsis by triggering the stimulator of interferon genes (STING) pathway, an intracellular DNA-sensing pattern recognition receptor, leading to remote organ injury [ 4 , 5 ]. However, a translation gap between studies of ALI due to clinical nonpulmonary insult and preclinical mtDNA-mediated immune cascade studies remains, as the mechanism underlying the development of lung injury from infection at a distant site is multifactorial and has not been well addressed.…”

Complement Initiation Varies by Sex in Intestinal Ischemia Reperfusion Injury

“…It is possible that the sexes may differ in the use of STING (stimulator of interferon genes) as a trigger of lipid peroxidation in intestinal IR. Although, the animal sex was not identified, STING appears to be critical in production of IR-induced eicosanoids, via Cox-2 and ALox, as well as cytokines ( 78 , 79 ). These data are supported by the increase in IL-10 and IL-12p40 but not IL-12p35 in a sepsis model of LPS and C5a ( 80 ).…”

The STING1 network regulates autophagy and cell death

“…Third, IL-22 induces STING1-dependent type I IFN and TNF expression in mouse small intestine organoids, driving necrosis 137 . Fourth, mtDNA-mediated STING1 signaling triggers necroptosis through synergistic IFN and TNF signaling in primary intestinal epithelial cells 138 . In sum, these data indicate that STING1 signaling triggers necroptosis through at least two mechanisms, inducing MLKL expression or MLKL phosphorylation.…”