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Nicotine inhibits the production of proinflammatory cytokines of mice infected with coxsackievirus B3

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Abstract

Aims

Although excessive sympathetic activation in viral myocarditis and the protective effects of sympathetic inhibition with β-blockers are clear, the effects of enhancing vagal tone on viral myocarditis remain unclear. In several models, vagus nerve activation with the α7 nicotinic acetylcholine receptor (α7-nAChR) agonists has been demonstrated to ameliorate inflammation. This study was therefore designed to examine the effects of cholinergic stimulation with α7-nAChR agonist nicotine in a murine model of acute viral myocarditis.

Materials and methods

BALB/C mice were infected by an intraperitoneally injection with coxsackievirus B3. Nicotine and methyllycaconitine (an α7-nAChR antagonist) were administered at doses of 0.4 mg/kg and 0.8 mg/kg three times per day for 7 or 14 consecutive days, respectively. The effects of nicotine and methyllycaconitine on survival rate, myocardial histopathological changes, cardiac function, cytokine levels, viral RNA, malondialdehyde, and superoxide dismutase contents were investigated.

Key findings

Nicotine significantly increased survival rate of the infected mice, decreased myocardial inflammation, and improved the impairment of left ventricular function in murine coxsackievirus B3-induced myocarditis compared with methyllycaconitine. The proinflammatory cytokines TNF-α, IL-1β, IL-6 and IL-17A were significantly decreased in the infected mice treated with nicotine compared with methyllycaconitine. Nicotine had no significant anti-oxidative and antiviral effects in coxsackievirus B3-infected mice.

Significance

The results indicate that cholinergic stimulation with nicotine significantly reduced the severity of viral myocarditis in mice. The findings suggest that alpha7 nAChR agonists may be a promising new strategy for patients with myocarditis.

Introduction

In humans, acute viral myocarditis is a potentially lethal disease and precedes the development of dilated cardiomyopathy [28]. The common infectious trigger of viral myocarditis is believed to be the enteroviruses of the picornavirus family, such as the coxsackie B virus group [3], [28]. Recent studies have revealed the roles played by various cytokines in the pathophysiology of viral myocarditis, and have found increased levels of circulating interleukin (IL)-1β, IL-6, IL-17A, tumor necrosis factor (TNF)-α, and other proinflammatory cytokines in patients with myocarditis [16], [23]. The roles of individual cytokines have also been studied in both animal models and humans [11], [29], [30], [31]. The exogenous administration of the proinflammatory cytokines aggravates myocarditis, and the neutralization of the proinflammatory cytokines by antibodies or soluble receptors and targeted disruption of the proinflammatory cytokines gene attenuate myocarditis.

Autonomic nervous system dysfunction, characterized by sympathetic activation and vagal withdrawal, is an important contributor to the progression of diverse cardiovascular disorders [41]. Recently, we have found that excessive sympathetic activation in viral myocarditis promotes inflammatory immune responses and aggravates inflammatory damage, and the β-blocker carvedilol was beneficial due to its upregulating the production of antiinflammatory cytokines and downregulating the production of proinflammatory cytokines [19], [37], [38], [39]. These findings suggest that the autonomic nervous system dysfunction also plays an important role in the pathogenesis of viral myocarditis. Despite these findings, it remains unclear whether vagus nerve stimulation protects against viral myocarditis.

Recently, Tracey and other researchers have identified the “cholinergic anti-inflammatory pathway” as a mechanism for the neuronal control of inflammation through the efferent vagus nerve [2], [32]. The efferent vagus nerve exerts antiinflammatory effects through the α7 nicotinic acetylcholine receptor (α7-nAChR), which is expressed not only by central nervous system–specific cells but also by immune cells such as macrophages and CD4+ T cells. Acetylcholine, the main parasympathetic neurotransmitter, is the endogenous agonist of α7-nAChR and is synthesized by both immune and nervous cells. Signaling of acetylcholine through α7-nAChR has been shown to reduce the levels of TNF-α, IL-1β, IL-6, and IL-17A by macrophages [2], [32]. However, it has been shown that nicotine, as a specific agonist of α7-nAChR, is more efficient than acetylcholine at reducing the levels of the proinflammatory cytokines by macrophages [33]. The protective effects of α7-nAChR agonists have been studied in a variety of models of inflammation, including sepsis [35], endotoxemia [27], ischemia reperfusion [24], hemorrhage [21], heart failure [41] and postoperative ileus [7]. Recently, we have also found that activation of the cholinergic anti-inflammatory pathway reduced inflammation in viral myocarditis [4]. However, the effects of α7-nAChR agonists and antagonists in viral myocarditis and on cytokine production are not well known. The present study was performed to compare the effects of the α7-nAChR agonist nicotine and the selective α7-nAChR antagonist methyllycaconitine in a murine model of viral myocarditis induced by coxsackievirus B3 (CVB3) infection.

Section snippets

Mice

Male BALB/c mice (4 weeks) were purchased from Shanghai Laboratory Animal Center of China. All mice were maintained in the Wenzhou Medical University animal facilities under specific pathogen-free conditions. All experiments were carried out more than three times. The study conformed with China Animal Protection Law. The Wenzhou Medical University Committee on Ethics in the Use and Care of Laboratory Animals approved the conduct of this study.

Virus infection

Animals were infected as described in our previous

Survival rate

On day 14, the survival rate of the myocarditis group (i.e., the infected untreated group) was 45.0%, while the nicotine group was 80.0%, the methyllycaconitine group was 40.0% (Fig. 1a). The survival rate was significantly increased in the nicotine compared to the methyllycaconitine group and myocarditis group (P < 0.05).

Hemodynamics of mice on days 7 and 14

The heart rates among the nicotine and methyllycaconitine and myocarditis groups on days 7 and 14 were similar (Fig. 1b). On days 7 and 14, the systolic blood pressure (SBP) of

Discussion

In the present study, we have studied the therapeutic effects of cholinergic stimulation with nicotine in viral myocarditis. Our results indicate that cholinergic stimulation with nicotine significantly reduced the severity of acute CVB3-induced myocarditis in mice. Nicotine treatment improved the 14-day survival of the infected mice, attenuated the myocardial lesions and improved the impairment of left ventricular function in murine viral myocarditis. More importantly, the proinflammatory

Competing interests

The authors declare that they have no competing interests.

Acknowledgement

This work is supported by the National Natural Science Foundation of China (grants No. 81570342 and No. 81200165) and the Zhejiang Provincial Natural Science Foundation of China (Grant No. Y14H310011) and the Wenzhou Municipal Science and Technology Commission, China (Grant No. Y20130038).

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