Cardiomyocyte IL-IR2 Protects Heart From Ischemia/Reperfusion Injury by Attenuating NLRP3 Inflammasome Activation and IL-17RA-Mediated Apoptosis

Abstract

Background: Myocardial ischemia reperfusion (I/R) is characterized by a complex inflammatory response that stimulates the formation of inflammasome and production of Interleukin-1β (IL-1β). As a decoy receptor for IL-1β, the role of Interleukin-1 receptor type 2 (IL-1R2) in myocardial I/R injury is still unclear. Here, for the first time, we report the underlying mechanisms of IL-1R2 in protecting cardiomyocyte against I/R injury. Methods: Initially, the expression of IL-1R2 in myocardial I/R injury was determined by RT-PCR and western blot assays. IL-1R2-deficiency mice and AAV-9 virus carrying IL-1R2 under cTnT promoter were administrated to identify the protective role of IL-1R2 and RNA-sequencing was performed to explore the underlying mechanisms of IL-1R2 in myocardial I/R injury. Besides, neonatal rat ventricular myocytes (NRVM) were isolated to investigate the relationships of IL-1R2, NLRP3 inflammasome and Interleukin 17 receptor A (IL-17RA). Findings: We demonstrated that the expression of IL-1R2 in cardiomyocyte was induced by I/R injury both in vivo and in vitro. IL-1R2-deficient mice decreased cardiac systolic function, increased infarct size and cardiomyocyte apoptosis. Whereas, Overexpression of IL-1R2 in cardiomyocyte protected cardiomyocyte against I/R-induced cell death through reducing the NLRP3 inflammasome activation and IL-17RA expression both in vivo and in vitro. Interpretation: Collectively, the upregulation of IL-1R2 in cardiomyocyte provides therapeutic effects in protecting cardiomyocyte against cell death during myocardial I/R injury. Funding: Natural Key Research and Development Project of Zhejiang Province, China (2018C03015), National Key Research and Development Program of China (2016YFC1102203), Zhejiang Provincial Natural Science Foundation of China under Grant (LQ17H020002). Declaration of Interests: The authors have declared that no conflict of interest exists. Ethics Approval Statement: The collection of blood plasma from AMI patients and healthy controls was conducted with approval from the Institutional Animal Care and Use Committee, and all animal studies were conducted with approval from the Medical Ethics Committee of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine.