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.
Highlights
The intestinal ischemia reperfusion (I/R) injury is a lifethreatening pathophysiological condition that commonly occurs in acute mesenteric ischemia, traumatic shock, hemorrhagic shock, sepsis, and some surgical procedures[1,2]
We found that circulating receptor-interacting protein kinase 3 (RIPK3) levels had a significant correlation with circulating Intestinal fatty acid-binding protein (I-FABP) and Dlactate levels (Fig. 1b, c), which points out the potential relationship between necroptosis and intestinal injury
Circulating RIPK3 had a positive correlation with biomarkers of intestinal injury (I-FABP and D-lactate), which points out a potential role of circulating RIPK3 in indicating intestinal injury
Summary
The intestinal ischemia reperfusion (I/R) injury is a lifethreatening pathophysiological condition that commonly occurs in acute mesenteric ischemia, traumatic shock, hemorrhagic shock, sepsis, and some surgical procedures[1,2]. This process eventually leads to the disruption of the mucosal barrier integrity on account of severe. Intestinal I/R injury causes the massive release of damage-associated molecular patterns (DAMPs) and subsequently leads to severe inflammatory responses[4]. Our team has found that mtDNA originated from intestinal epithelial cells (IECs) exacerbates the inflammatory responses and gut barrier dysfunction during intestinal I/R injury[6]. The function and explicit sensors of mtDNA in intestinal I/R injury have not yet been clarified
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