IL-37 alleviates Coxsackievirus B3-induced viral myocarditis: possible relationship with inhibiting NLRP3 inflammasome-mediated pyroptosis and NF-κB, and increasing IL-37-IL-1R8-IL-18RA complex

IL-37 is identified as a novel anti-inflammatory cytokine, which has been shown to alleviate several autoimmune diseases. Our study aims to verify the potential effects and underlying mechanisms of IL-37 in Coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC). We established the VMC model by intraperitoneal injection of CVB3 on day 0. IL-37 was injected on day 4 and day 7. The cardiac function was evaluated by transthoracic echocardiography on day 9. Myocardial injury was measured by Elisa for serum cTnI. The inflammation infiltration and fibrosis were evaluated by hematoxylin and eosin (HE) staining and Masson staining. The expression levels of NLRP3, ASC dimer, cleaved caspase 1, IL-1β, IL-18, and Gasdermin D (GSDMD) were determined by western blot, Elisa, and immunofluorescent analysis. Compared with the VMC group, mice received CVB3 and IL-37 have improved cardiac function and reduced inflammation infiltration and fibrosis. Compared with the VMC group, we observed lower expression of cTnI, IL-1β, IL-18 and NLRP3 inflammasome component in mice received CVB3 and IL-37 by Elisa and western blot. And IL-37 treatment notably weakened the upregulation of GSDMD induced by CVB3. And IL-37 significantly weakened the up-regulation and phosphorylation of NF-κB p65 induced by CVB3. We also found that exogenous addition of IL-37 further increases the production of IL-37-IL-1R8 -IL-18RA complex on the basis of CVB3 in vitro. Our findings indicate that IL-37 alleviates CVB3-induced VMC, which may be produced by inhibiting NLRP3 inflammasome-mediated pyroptosis, NF-κB signaling pathway, and IL-37-IL-1R8 -IL-18RA complex.