Abstract
BackgroundInterleukin (IL)-38, a novel member of the IL-1 family, has been reported to be involved in several diseases associated with viral infection. However, the expression and functional role of IL-38 in acute viral myocarditis (AVMC) have not been investigated.MethodsMale BALB/c mice were treated with intraperitoneal (i.p.) injection of coxsackievirus B3 (CVB3) for establishing AVMC models. On day 7 post-injection, the expression of IL-38 and IL-36R (IL-36 receptor) were measured. Mice were then treated with i.p. injection of mouse Anti-IL-38 Antibodies (Abs) for neutralization of IL-38. The survival, bodyweight loss, cardiac function, and myocarditis severity of mice were recorded. The percentages of splenic Th1 and Th17 cells, the expression levels of Th1/Th17-related master transcription factors (T-bet and RORγt) and cytokines were determined by flow cytometry, RT-qPCR, and ELISA, respectively. Cardiac viral replication was further detected.ResultsThe mRNA and protein expression levels of IL-38 in myocardium and serum, as well as cardiac IL-36R mRNA levels were significantly elevated in mice with AVMC. Increased IL-38 levels were negatively correlated with the severity of AVMC. Neutralization of IL-38 exacerbated CVB3-induced AVMC, as verified by the lower survival rate, impaired cardiac function, continuous bodyweight loss, and higher values of HW/BW and cardiac pathological scores. In addition, neutralization of IL-38 suppressed Th1 cells differentiation while promoted Th17 cells differentiation, accompanied by decreased T-bet mRNA expression and increased RORγt expression. Down-regulation of IFN-γ and up-regulation of IL-17, TNF-α, and IL-6 mRNA and protein expression levels in myocardium and serum were also observed in the IL-38 neutralization group. Furthermore, neutralization of IL-38 markedly promoted cardiac viral replication.ConclusionsNeutralization of IL-38 exacerbates CVB3-induced AVMC in mice, which may be attributable to the imbalance of Th1/Th17 cells and increased CVB3 replication. Thus, IL-38 can be considered as a potential therapeutic target for AVMC.
Highlights
Interleukin (IL)-38, a novel member of the IL-1 family, has been reported to be involved in several diseases associated with viral infection
Gao and Conti have reported that IL-38 is a potential therapeutic cytokine that inhibits inflammation in viral infections, including those caused by the influenza virus and Coronavirus-19 [17, 18]. These findings indicate that IL-38 may play an important role in the pathogenesis of diseases associated with viral infection
Based on the observation that the levels of IL-38 and Interleukin-36 receptor (IL-36R) were elevated in acute viral myocarditis (AVMC), and that the IL-38 levels showed a negative correlation with the severity of AVMC, we tentatively explored the potential role of IL-38 in a mouse model of AVMC with the use of Anti-IL-38 Abs in vivo
Summary
Interleukin (IL)-38, a novel member of the IL-1 family, has been reported to be involved in several diseases associated with viral infection. Acute viral myocarditis (AVMC), a common inflammatory myocardial disease, is one of the leading causes of acute-onset heart failure and sudden death among young patients [1, 2]. Some patients with AVMC may progress into chronic myocarditis, causing continuous destruction of cardiomyocytes and the initiation of remodeling. Coxsackievirus B3 (CVB3), a member of the Picornaviridae family, has been identified as the most common pathogen for AVMC [4]. A multitude of studies have demonstrated that the major pathogenesis of AVMC is excessively uncontrolled inflammatory responses triggered by myocardial damage following viral infection, the direct attack of the virus on cardiomyocytes is considered a critical component for AVMC development and progression [5, 6]. It is essential to clarify the fundamental mechanisms responsible for AVMC
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