Abstract
BackgroundRecently, a new subset of T helper (Th) cell that predominantly secret cytokine interleukin-22 (IL-22) is identified, termed Th22 cells. The Th22 subset has been demonstrated to be involved in immunity and tissue inflammation. However, the existence of Th22 cells and role of IL-22 in acute viral myocarditis (AVMC) remain unknown.MethodsBALB/c mice were intraperitoneally (i.p) infected with CVB3 for establishing AVMC models. Control mice were treated with phosphate-buffered saline (PBS) i.p. On day 14 post injection, frequencies of splenic Th22 cells were determined, productions of IL-22 and expressions of IL-22R (IL-22 receptor) were measured. To further investigate the effects of IL-22, AVMC mice treated with Anti-IL-22 neutralizing antibody were explored. The severity of AVMC were monitored; the frequencies of Th22 cells, the expressions of IL-22 and IL-22R were investigated; in addition to IFN-γ, inflammatory cytokines IL-17, TNF-α, IL-6 as well as IL-1β, were evaluated. Cardiac viral replication were detected.ResultsCompared with control group, significant elevations of circulating Th22 cells and IL-22, cardiac protein and mRNA of IL-22, and IL-22R1 were demonstrated in AVMC group. Treatment of AVMC mice with Anti-IL-22 Ab exacerbated the severity of viral myocarditis, verified by lower survival rate, higher HW/BW ratios and cardiac pathological scores. Anti-IL-22 Ab decreased the frequencies of Th22 cells and the levels of IL-22, and increased the expressions of cardiac IL-22R1. Up-regulations of IL-17, IL-6 and TNF-α, down-regulations of IFN-γ proteins and gene expressions in the plasma and myocardium, were observed in Anti-IL-22 Ab group. Furthermore, neutralization of IL-22 significantly promoted cardiac viral replication.ConclusionsOur data indicate that the increased frequencies of IL-22-producing Th22 cells may play an important role in the pathogenesis of CVB3-induced mice AVMC, IL-22 may act as an myocardium-protective cytokine via the IL-22–IL-22R pathway, and suggest that targeting the Th22 cell and IL-22–IL-22R pathway could provide new therapeutic modalities for the treatment of CVB3-induced AVMC.
Highlights
A new subset of T helper (Th) cell that predominantly secret cytokine interleukin-22 (IL-22) is identified, termed Th22 cells
Neutralization of IL-22 exacerbated the severity of acute viral myocarditis (AVMC) As shown in Figure 3, the results showed that AntiIL-22Ab accelerated the development of myocarditis and exacerbated the severity
To explore the role of this pathway in AVMC, we firstly investigated the expressions of cardiac IL-22 and Interleukin-22 receptor (IL-22R), the latter which consists of IL22R1 and IL-10R2
Summary
A new subset of T helper (Th) cell that predominantly secret cytokine interleukin-22 (IL-22) is identified, termed Th22 cells. The Th22 subset has been demonstrated to be involved in immunity and tissue inflammation. The existence of Th22 cells and role of IL-22 in acute viral myocarditis (AVMC) remain unknown. Acute viral myocarditis (AVMC) is characterized by myocardial inflammation and can progress to chronic dilated cardiomyopathy (DCM), a terminal condition requiring transplantation. Accumulating data had indicated the dominant cause of myocardial cells damage in AVMC were inflammation and autoimmune responses triggered by the viral infection, mediated by T cells and their cytokines [1,2,3]. Emerging evidence have demonstrated that several Th subsets, such as Th1, Treg, Th17 but not Th9 cells, are involved in the pathogenesis of AVMC [4,5,6,7,8]. The fundamental mechanisms responsible for AVMC are not completely clarified, and therapeutics for AVMC are restricted to supportive care including basic medications [9]
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