Protective Role of the Cholinergic Anti-Inflammatory Pathway in a Mouse Model of Viral Myocarditis

Abstract

BackgroundActivation of the cholinergic anti-inflammatory pathway, which relies on the α7nAchR (alpha 7 nicotinic acetylcholine receptor), has been shown to decrease proinflammatory cytokines. This relieves inflammatory responses and improves the prognosis of patients with experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, pancreatitis, arthritis and other inflammatory syndromes. However, whether the cholinergic anti-inflammatory pathway has an effect on acute viral myocarditis has not been investigated. Here, we studied the effects of the cholinergic anti-inflammatory pathway on acute viral myocarditis.Methodology/Principal FindingsIn a coxsackievirus B3 murine myocarditis model (Balb/c), nicotine and methyllycaconitine were used to stimulate and block the cholinergic anti-inflammatory pathway, respectively. Relevant signal pathways were studied to compare their effects on myocarditis, survival rate, histopathological changes, ultrastructural changes, and cytokine levels. Nicotine treatments significantly improved survival rate, attenuated myocardial lesions, and downregulated the expression of TNF-α and IL-6. Methyllycaconitine decreased survival rate, aggravated myocardial lesions, and upregulated the expression of TNF-α and IL-6. In addition, levels of the signaling protein phosphorylated STAT3 were higher in the nicotine group and lower in the methyllycaconitine group compared with the untreated myocarditis group.Conclusions/SignificanceThese results show that nicotine protects mice from CVB3-induced viral myocarditis and that methyllycaconitine aggravates viral myocarditis in mice. Because nicotine is a α7nAchR agonist and methyllycaconitine is a α7nAchR antagonist, we conclude that α7nAchR activation increases the phosphorylation of STAT3, reduces the expression of TNF-α and IL-6, and, ultimately, alleviates viral myocarditis. We also conclude that blocking α7nAchR reduces the phosphorylation of STAT3, increases the expression of TNF-α and IL-6, aggravating viral myocarditis.

Salidroside Mitigates Sepsis-Induced Myocarditis in Rats by Regulating IGF-1/PI3K/Akt/GSK-3β Signaling

“…Inflammation has been recognized as a major driving force in the ischemic process, and increasing evidence has shown that enhanced levels of inflammatory markers are related to myocardial inflammation [20,21]. Proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6, are small secreted proteins that mediate and regulate inflammation.…”

The cholinergic anti-inflammatory pathway ameliorates acute viral myocarditis in mice by regulating CD4+ T cell differentiation

“…Although the anti-inflammatory effect of CAP on VMC has been demonstrated in previous studies from our group and others [6–8,12], it has not been reported whether CAP can affect the differentiation of CD4 + T cell subsets. However, based on previous studies, we hypothesized that CAP could inhibit the inflammatory response by modulating the differentiation of Th cells subsets in VMC, and reducing myocardium lesions.…”

“…The CAP is a recently proposed immunoregulatory pathway that inhibits the release of inflammatory cytokines by connecting the nervous system to the immune system, ameliorating the inflammatory response of many diseases, such as sepsis, ulcerative colitis, and rheumatoid arthritis. Our previous studies have indicated that the CAP significantly decreases the level of Th17 cell-related IL-17A and IL-6 as well as Th1 cell-associated TNF-α [6–10]. Galitovskiy et al also found that α7-nicotinic acetylcholine receptor (α7-nAChR) agonist, nicotine, increased the ratio of Treg cells and reduced the ratio of Th17 cells, improving the prognosis of ulcerative colitis [11].…”

Interaction between the hypothalamus and the immune system

“…pathway' as the efferent arm of the inflammatory reflex (Pavlov & Tracey, 2012) based on the observation that electrical stimulation of the vagus decreased plasma TNFα concentrations after LPS administration. Additionally, the protective role of the vagus in models of inflammation other than endotoxaemia, such as ischaemia-reperfusion injury (Jiang et al 2014), viral myocarditis (Cheng et al 2014) and postoperative ileus , has been clearly shown. However, it is important to note that all these studies used pharmacological or electrical approaches to activate the vagus.…”

“…), viral myocarditis (Cheng et al . ) and postoperative ileus (The et al . ), has been clearly shown.…”