Interleukin-37 alleviates myocardial injury induced by coxsackievirus B3 via inhibiting neutrophil extracellular traps formation

Objective: To investigate whether interleukin-37 (IL-37) could directly inhibit the formation of neutrophil extracellular traps (NETs) in the early stage of acute viral myocarditis (VMC) and its potential mechanisms of action.

Methods: Acute VMC was induced by intraperitoneally injecting coxsackievirus B3 (CVB3)(10³ TCID50) in mice on day 0. Mice were injected with AAV9-IL-37 or AAV9-NC through the caudal vein 1 week before intraperitoneal administration of CVB3. DNASE1 (50ug per mouse) was administered on days 0 to 7 to investigate the role of NETs formation during acute VMC. The severity of myocardial inflammation was evaluated by observing the general condition of mice and detecting cardiac histopathology. Moreover, neutrophils isolated from healthy human peripheral blood were stimulated by phorbol myristate acetate (PMA 100 nM) and treated with IL-37 (0.1 ng/ml) or BAY11-7082(2.5uM) in vitro. The production of NETs was detected by immunofluorescence labeled MPO and DNA. The expression of related proteins (IκBα, P-IκBα, NFκb, P-NFκb) was detected by Western blot.

Results: The results showed that, like DNASE1, IL-37 alleviates the symptoms in acute VMC induced by CVB3, reduces inflammatory cell infiltration, improves cardiac function, and inhibits the formation of NETs in the myocardium. Besides, both IL-37 and DNASE1 could effectively inhibit the activation of NFκb /IκBα. In the isolated peripheral blood neutrophils, the inhibitory effect of IL-37 on the formation of NETs and the activation of NFκb /IκBα was further confirmed.

Conclusion: IL-37 has a protective effect on VMC by reducing the infiltration of inflammatory cells and inhibiting the formation of NETs at an early phase.

Coxsackievirus B3; DNASE1; Interleukin-37; NFκb /IκBα; Neutrophil extracellular traps; Viral myocarditis.