Vagal afferent fibers contribute to the anti-inflammatory reactions by vagus nerve stimulation in concanavalin A model of hepatitis in rats

Abstract

Background Increasing number of studies provide evidence that the vagus nerve stimulation (VNS) dampens inflammation in peripheral visceral organs. However, the effects of afferent fibers of the vagus nerve (AFVN) on anti-inflammation have not been clearly defined. Here, we investigate whether AFVN are involved in VNS-mediated regulation of hepatic production of proinflammatory cytokines. Methods An animal model of hepatitis was generated by intraperitoneal (i.p.) injection of concanavalin A (ConA) into rats, and electrical stimulation was given to the hepatic branch of the vagus nerve. AFVN activity was regulated by administration of capsaicin (CAP) or AP-5/CNQX and the vagotomy at the hepatic branch of the vagus nerve (hVNX). mRNA and protein expression in target tissues was analyzed by RT-PCR, real-time PCR, western blotting and immunofluorescence staining. Hepatic immune cells were analyzed by flow cytometry. Results TNF-α, IL-1β, and IL-6 mRNAs and proteins that were induced by ConA in the liver macrophages were significantly reduced by the electrical stimulation of the hepatic branch of the vagus nerve (hVNS). Alanine transaminase (ALT) and aspartate transaminase (AST) levels in serum and the number of hepatic CD4+ and CD8+ T cells were increased by ConA injection and downregulated by hVNS. CAP treatment deteriorated transient receptor potential vanilloid 1 (TRPV1)-positive neurons and increased caspase-3 signals in nodose ganglion (NG) neurons. Concomitantly, CAP suppressed choline acetyltransferase (ChAT) expression that was induced by hVNS in DMV neurons of ConA-injected animals. Furthermore, hVNS-mediated downregulation of TNF-α, IL-1β, and IL-6 expression was hampered by CAP treatment and similarly regulated by hVNX and AP-5/CNQX inhibition of vagal feedback loop pathway in the brainstem. hVNS elevated the levels of α7 nicotinic acetylcholine receptors (α7 nAChR) and phospho-STAT3 (Tyr705; pY-STAT3) in the liver, and inhibition of AFVN activity by CAP, AP-5/CNQX and hVNX or the pharmacological blockade of hepatic α7 nAChR decreased STAT3 phosphorylation. Conclusions Our data indicate that the activity of AFVN contributes to hepatic anti-inflammatory responses mediated by hVNS in ConA model of hepatitis in rats.

Vagus nerve stimulation alleviated cerebral ischemia and reperfusion injury in rats by inhibiting pyroptosis via α7 nicotinic acetylcholine receptor

“…In turn, the dorsal nucleus activates the efferent branch of VN to release acetylcholine, which binds to the α7 nicotinic acetylcholine receptor (α7nAchR) for its anti-inflammatory function [ 14 , 15 ]. α7nAchR, the most crucial molecule in CAP, can be activated and upregulated by VNS-induced endogenous acetylcholine [ 16 ]. Reportedly, α7nAchR-mediated CAP is closely related to many diseases in the central nervous system (CNS).…”

Vagus nerve stimulation modulates hippocampal inflammation caused by continuous stress in rats

“…After the CS, rats were anesthetized with ketamine (80 mg/kg; Yuhan, Seoul, Korea) and xylazine (5 mg/kg; Bayer, Leverkusen, Germany). VNS in rats was given as described in our previous study [ 12 , 21 ]. Briefly, the anterior surface of the neck and the muscles were incised and the larynx was lifted.…”

“…Here, acetylcholine neurotransmitters released from the efferent fibers of the vagus nerve interact with ɑ7 nicotinic acetylcholine receptors (ɑ7 nAChR) in target cells (e.g., splenic macrophages) and subsequently induce the JAK2 activation of STAT3 and NF-kB leading to the inhibition of the expression of proinflammatory cytokine genes [ 8 , 9 ]. Since VNS is given to the exposed nerve in experimental animals, anti-inflammatory effects can also be influenced by afferent nerve activity through feedback loop in the dorsal vagal complex [ 10 – 12 ]. Moreover, VNS acting on the ascending fibers that transmit signals to the forebrain was reported to enhance memory formation and improve mental illnesses such as epilepsy and depression [ 13 – 15 ].…”

“…Ascending vagus nerve activity may be involved in activating brainstem nuclei for neuromodulation and affect the limbic system and cerebral cortex, modulating emotional and cognitive function in the brain [ 7 ]. We have recently reported that the afferent component of VNS increased cholinergic nerve activity in the dorsal vagal complex and resulted in the upregulation of α7 nAChR levels in the liver [ 12 ]. α7 nAChR activity in the brain was shown to participate in the regulation of NMDA and GABA receptor activation and correlate with the occurrence of Schizophrenia [ 17 – 19 ].…”

Cholinergic anti-inflammatory pathway ameliorates murine experimental Th2-type colitis by suppressing the migration of plasmacytoid dendritic cells

“…It has been reported that JAK2-STAT3 pathway is involved in cholinergic anti-inflammatory effects through α7nAChRs after vagus nerve stimulation in macrophages 9 , 12 and liver cells 23 . However, STAT3 negatively regulates inflammatory responses primarily through anti-inflammatory effects of IL-10, an anti-inflammatory cytokine, without directly suppressing transcription of pro-inflammatory cytokines 24 .…”