Neutralization of interleukin-38 exacerbates coxsackievirus B3-induced acute myocarditis in mice

Abstract

Background Interleukin (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. Methods Male 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. Results The 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. Conclusions Neutralization 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.

The emerging role of IL‐38 in diseases: A comprehensive review

“…In sepsis mice model, the level of IL‐38 increased and IL‐38 could prolong the survival of mice. 53 Xue et al 54 demonstrated that the neutralization of IL‐38 exacerbated coxsackievirus B3‐induced viral myocarditis (AVMC) in mice, possibly due to a Th1/Th17 cell imbalance and elevated virus replication. These findings indicate that IL‐38 plays a protective role during pathogen infection and is a potential therapeutic target for infectious diseases.…”

Serum IL-38 Level Was Associated with Incidence of MACE in the STEMI Patients

“…In addition, neutralizing IL-38 antibodies significantly exacerbated heart failure and significantly increased mortality in mice with myocarditis, and further study of the mechanism revealed that this may be achieved through inhibition of th17 cell differentiation. 51 Secondly, Wei et al reported that, in the anterior descending ligation mouse model, the level of IL-38 was significantly elevated. However, exogenous supplementation of IL-38 significantly improved cardiac ejection function and inhibited cardiac remodeling in mice, the underlying mechanism may be the inhibition of dendritic cell hyperactivation.…”

Exploratory analysis of interleukin‐38 in hospitalized COVID‐19 patients

“…Evidence of IL‐38's acute role in response to local or systemic infections, however, is scarce. In mice infected with coxsackievirus B3, neutralization of IL‐38 reduced survival and cardiac function and was associated with increased viral replication 26 . In murine models of sepsis, IL‐38 administration decreased inflammatory cytokines and organ damage and augmented bacterial clearance 27 .…”

“…In mice infected with coxsackievirus B3, neutralization of IL‐38 reduced survival and cardiac function and was associated with increased viral replication. 26 In murine models of sepsis, IL‐38 administration decreased inflammatory cytokines and organ damage and augmented bacterial clearance. 27 In humans, IL‐38 plasma concentrations were elevated in patients with sepsis, which negatively correlated to circulating proinflammatory cytokines and blood leukocyte counts.…”