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

• DOI: 10.21203/rs.2.23662/v1
• Publication Date: 2020-02-17T15:45:32Z
• Authors: Dejun Kong; Yonghao Hu; Xiang Li; Dingding Yu; Hongyue Li; Yiming Zhao; Yafei Qin; Wang Jin; Baoren Zhang; Bo Wang; Hongda Wang; Guangming Li; Hao Wang
• Keywords: 0301 basic medicine; 0303 health sciences; 03 medical and health sciences; Internal medicine; RC31-1245; Research Article; 3. Good health

Abstract 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) showed some beneficial roles to ameliorate IRI, their effects are limited. In this study, the protective effects of IL-37 gene-modified MSCs (IL-37-MSCs) for better prevention of intestinal IRI are investigated.Methods: Intestinal IRI model was established by occluding the superior mesenteric artery for 30min and then reperfusing for 72 hours in rats. Forty adult male SD rats were randomly divided into 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 reactivity cytokine IL-1β were assayed by ELISA. The expressions of tissue damage-related NLRP3 inflammasome and relative proteins including clevead caspase-1, IL-1β and IL-18 were detected by western blot. As downstream of IL-1β and IL-18, the mRNA levels of proinflammatory mediators IL-6 and TNF-α were determined by qPCR. Data were analyzed by one-way analysis of variance among groups.Results: IL-37-MSCs were able to migrate to the damaged tissue and significantly inhibit intestinal IRI. As compared with MSCs or rIL-37 monotherapy group, IL-37-MSC treatment not only improved gut barrier function but also decreased local and systemic inflammation reactivity cytokine IL-1β level in IRI rats. In addition, tissue damage-related NLRP3 and relative proteins (cleaved caspase-1, IL-1β and 4 IL-18) were significantly decreased in IRI rats treated with IL-37-MSCs. Furthermore, IL-1β and IL-18 related proinflammatory mediators IL-6 and TNF-α mRNA expressions were markedly decreased following IL-37-MSC treatment.Conclusion: The results suggest that IL-37 gene modification significantly enhance the protective effects of MSCs against intestinal IRI. In addition, NLRP3-related signaling pathways could be associated with IL-37-MSC mediated protection.