Involvement of MAPK/NF-κB Signaling in the Activation of the Cholinergic Anti-Inflammatory Pathway in Experimental Colitis by Chronic Vagus Nerve Stimulation

Abstract

BackgroundAutonomic nervous system dysfunction is implicated in the etiopathogenesis of inflammatory bowel diseases (IBD). Therapies that increase cardiovagal activity, such as Mind-Body interventions, are currently confirmed to be effective in clinical trials in IBD. However, a poor understanding of pathophysiological mechanisms limits the popularization of therapies in clinical practice. The aim of the present study was to explore the mechanisms of these therapies against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats using a chronic vagus nerve stimulation model in vivo, as well as the lipopolysaccharide (LPS)-induced inflammatory response in human epithelial colorectal adenocarcinoma cells (Caco-2) by acetylcholine in vitro.Methods and ResultsColitis was induced in rats with rectal instillation of TNBS, and the effect of chronic VNS (0.25 mA, 20 Hz, 500 ms) on colonic inflammation was evaluated. Inflammatory responses were assessed by disease activity index (DAI), histological scores, myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS), TNF-α and IL-6 production. The expression of Mitogen-activated protein kinases (MAPK) family members, IκB-α, and nuclear NF-κB p65 were studied by immunoblotting. Heart rate variability (HRV) analysis was also applied to assess the sympathetic-vagal balance. DAI, histological scores, MPO activity, iNOS, TNF-α and IL-6 levels were significantly decreased by chronic VNS. Moreover, both VNS and acetylcholine reduced the phosphorylation of MAPKs and prevented the nuclear translocation of NF-κB p65. Methyllycaconitine (MLA) only reversed the inhibitory effect on p-ERK and intranuclear NF-κB p65 expression by ACh in vitro, no significant change was observed in the expression of p-p38 MAPK or p-JNK by MLA.ConclusionVagal activity modification contributes to the beneficial effects of the cholinergic anti-inflammatory pathway in IBD-related inflamed colonic mucosa based on the activation of MAPKs and nuclear translocation of NF-κB. Our work may provide key pathophysiological mechanistic evidence for novel therapeutic strategies that increase the cardiovagal activity in IBD patients.

Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes

“…In animal models, VNS has been evaluated as a therapy in various diseases, such as sepsis, hemorrhagic shock, IBD, IRI in brain and heart, and arthritis (11,20). In rats, α7nAChR agonists reduce kidney IRI (21), but the effect of VNS on kidney injury and the underlying mechanisms have not been examined.…”

Exercise, fitness, and the gut

“…The benefits of VNS may reach beyond its established roles in intractable epilepsy and treatment-resistant depression [36,37]. There is experimental evidence for the use of VNS in inflammatory conditions, particularly rheumatoid arthritis [38,39] and IBD [40,41]. However, prospective controlled trials are pending.…”

Anti-inflammatory effect of a standardized triterpenoid-rich fraction isolated from Rubus coreanus on dextran sodium sulfate-induced acute colitis in mice and LPS-induced macrophages

“…In particular, p38 MAPK triggers the transcriptional activation of NF-κB via the phosphorylation of p65 (Kefaloyianni et al, 2006;Shin et al, 2011a). Furthermore, the activity of p38 MAPK is higher in IBD patients than in normal controls (Vallabhapurapu and Karin, 2009) and phosphorylated p38 MAPK levels were reported to be elevated in experimental colitis model (Sun et al, 2013). Interestingly, immunohistochemical analysis of the inflamed mucosal biopsies of IBD patients showed that p38 MAPK and NF-κB were mainly localized in lamina propria macrophages and neutrophils (Luhrs et al, 2002;Waetzig et al, 2002).…”