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) 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.
Highlights
Intestinal ischemia reperfusion injury (IRI), one of the major causes of clinical acute intestine necrosis, is a life-threatening disease with high mortality and disability [1]
The NOD-like receptor protein 3 (NLRP3)-mediated proinflammatory signaling pathway was found to be upregulated in the untreated Ischemia reperfusion injury (IRI) group, which was significantly suppressed following mesenchymal stromal cells (MSCs), rIL-37, and IL37-MSC treatments, suggesting the multifactorial nature of underlying mechanisms involved in intestinal IRI, for which interleukin 37 (IL-37)-MSCs demonstrated much more powerful effects than MSCs or rIL-37 alone in attenuation of intestinal IRI
Untreated Intestine IL-6 mRNA expression fold treated group) to help better inhibit NLRP3 inflammasome activation to alleviate damage, thereby enhancing the effects of MSCs in the intestinal IRI model. This is the first study to demonstrate that IL-37 could play a protective role in the intestinal IRI and illustrated that IL-37 gene modification could enhance the therapeutic effects of MSCs in the ischemia reperfusion injury
Summary
Intestinal ischemia reperfusion injury (IRI), one of the major causes of clinical acute intestine necrosis, is a life-threatening disease with high mortality and disability [1]. Ischemia reperfusion injury (IRI) is the major cause of intestinal damage in clinic. 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. 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. 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. NLRP3-related signaling pathways could be associated with IL-37-MSC-mediated protection
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