IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

BACKGROUND: Ischemia reperfusion injury (IRI) is the major cause of intestinal damage in clinic. Although either mesenchymal stromal cells (MSCs) or interleukin 37 (IL-37) shows some beneficial roles to ameliorate IRI, their effects are limited. In this study, the preventative effects of IL-37 gene-modified MSCs (IL-37-MSCs) on intestinal IRI are investigated. METHODS: Intestinal IRI model was established by occluding the superior mesenteric artery for 30 minutes and then reperfused for 72 hours in rats. Forty adult male Sprague-Dawley rats were randomly divided into the sham control, IL-37-MSC-treated, MSC-treated, recombinant IL-37- (rIL-37-) treated, and untreated groups. Intestinal damage was assessed by H&E staining. The levels of gut barrier function factors (diamine oxidase and D-Lactate) and inflammation cytokine IL-1β were assayed using ELISA. The synthesis of tissue damage-related NLRP3 inflammasome and downstream cascade reactions including cleaved caspase-1, IL-1β, and IL-18 was detected by western blot. The mRNA levels of proinflammatory mediators IL-6 and TNF-α, which are downstream of IL-1β and IL-18, were determined by qPCR. Data were analyzed by one-way analysis of variance (ANOVA) after the normality test and followed by post hoc analysis with the least significant difference (LSD) test. RESULTS: IL-37-MSCs were able to migrate to the damaged tissue and significantly inhibit intestinal IRI. As compared with MSCs or the rIL-37 monotherapy group, IL-37-MSC treatment both improved gut barrier function and decreased local and systemic inflammation cytokine IL-1β level in IRI rats. In addition, tissue damage-related NLRP3 and downstream targets (cleaved caspase-1, IL-1β, and IL-18) were significantly decreased in IRI rats treated with IL-37-MSCs. Furthermore, IL-1β- and IL-18-related proinflammatory mediator IL-6 and TNF-α mRNA expressions were all significantly decreased in IRI rats treated with IL-37-MSCs. CONCLUSION: The results suggest that IL-37 gene modification significantly enhances the protective effects of MSCs against intestinal IRI. In addition, NLRP3-related signaling pathways could be associated with IL-37-MSC-mediated protection.