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

Abstract

Many studies have found that abnormalities in the proportion and differentiation of CD4+ T cells (Th cells) are closely related to the pathogenesis of viral myocarditis (VMC). Our previous research indicates that the cholinergic anti-inflammatory pathway (CAP) attenuates the inflammatory response of VMC and downregulates the expression of cytokines in Th1 and Th17 cells. This suggests that the cholinergic anti-inflammatory pathway likely attenuates the inflammatory response in VMC by altering Th cell differentiation. The aim of this study is to investigate the effect of CAP on CD4+ T cell differentiation in VMC mice. CD4+ T cells in the spleen of VMC mice were obtained and cultured in the presence of nicotine or methyllycaconitine (MLA). Cells were harvested and analyzed for the percentage of each Th cell subset by flow cytometry and transcription factor release by Western blot. Then, we detected the effect of CAP on the differentiation of Th cells in vivo. Nicotine or MLA was used to activate and block CAP, respectively, in acute virus-induced myocarditis. Nicotine treatment increased the proportion of Th2 and Treg cells, decreased the proportion of Th1 and Th17 cells in the spleen, reduced the level of proinflammatory cytokines, and attenuated the severity of myocardium lesions and cellular infiltration in viral myocarditis. MLA administration had the opposite effect. Our result demonstrated that CAP effectively protects the myocardium from virus infection, which may be attributable to the regulation of Th cell differentiation.

Blocking the Hepatic Branch of the Vagus Aggravates Hepatic Ischemia-Reperfusion Injury via Inhibiting the Expression of IL-22 in the Liver

“…Vagus nerve stimulation has been at the forefront of inflammatory disease research, and there have been many promising results [19][20][21]. Many studies have reported that the vagus nerve regulates the immune response effectively, a concept known as the cholinergic anti-inflammatory pathway [22][23][24][25]. The protective effect of vagus nerve signaling on IR injury in different organs of animals, including the myocardium and brain, has been reported [12,[26][27].…”

Effects of Transcutaneous Auricular Vagus Nerve Stimulation on Peripheral and Central Tumor Necrosis Factor Alpha in Rats with Depression-Chronic Somatic Pain Comorbidity

“…And α 7nAChR is a key protein of signals triggered by VNS to induce the endogenous CAP [ 28 ]. Ach activates α 7nAChR on macrophages, lymphocytes, and other inflammatory cells, regulating the synthesis and release of inflammatory cytokines and relieving the systemic inflammatory reaction [ 30 ]. The anti-inflammatory effects of taVNS and EA at ST 36 are closely related to the vagus-mediated cholinergic pathway.…”

COVID-19-related myocarditis and cholinergic anti-inflammatory pathways

“… 72 In monocytes, α7nAChR activated by non- or strong agonists downregulates NF-κB nuclear translocation and TLR4 expression, and suppresses transcription of pro-inflammatory cytokines. 29 , 36 , 75 De-Pu and colleagues 76 have used nicotine to activate α7nAChR in mice with acute virus-induced myocarditis. The proportion of Th2 and Treg cells increased, and that of Th1 and Th17 cells decreased in the spleen, thus indicating that the α7 subunit is essential for cholinergic suppression of TNF-α and the normal regulation of systemic inflammatory responses.…”

“…Importantly, the CAP has been shown to decrease the inflammatory response in viral myocarditis. 76 , 86 Activated α7nAChR by nicotine improves the balance of Th1/Th2 and Th17/Treg cell functional axis 76 and significantly down-regulates the expression of TNF-α and IL-6 in mice with CVB3-induced viralmyocarditis. 86 In addition, α7nAChR plays an important role in the expression of ACE-2, the target receptor of SARS-CoV-2.…”