Abstract
BackgroundThe cholinergic anti-inflammatory pathway (CAP) is based on vagus nerve (VN) activity that regulates macrophage and dendritic cell responses in the spleen through alpha-7 nicotinic acetylcholine receptor (a7nAChR) signaling. Inflammatory bowel disease (IBD) patients present dysautonomia with decreased vagus nerve activity, dendritic cell and T cell over-activation. The aim of this study was to investigate whether central activation of the CAP alters the function of dendritic cells (DCs) and sequential CD4+/CD25−T cell activation in the context of experimental colitis.MethodsThe dinitrobenzene sulfonic acid model of experimental colitis in C57BL/6 mice was used. Central, intracerebroventricular infusion of the M1 muscarinic acetylcholine receptor agonist McN-A-343 was used to activate CAP and vagus nerve and/or splenic nerve transection were performed. In addition, the role of α7nAChR signaling and the NF-kB pathway was studied. Serum amyloid protein (SAP)-A, colonic tissue cytokines, IL-12p70 and IL-23 in isolated splenic DCs, and cytokines levels in DC-CD4+CD25−T cell co-culture were determined.ResultsMcN-A-343 treatment reduced colonic inflammation associated with decreased pro-inflammatory Th1/Th17 colonic and splenic cytokine secretion. Splenic DCs cytokine release was modulated through α7nAChR and the NF-kB signaling pathways. Cholinergic activation resulted in decreased CD4+CD25−T cell priming. The anti-inflammatory efficacy of central cholinergic activation was abolished in mice with vagotomy or splenic neurectomy.ConclusionsSuppression of splenic immune cell activation and altered interaction between DCs and T cells are important aspects of the beneficial effect of brain activation of the CAP in experimental colitis. These findings may lead to improved therapeutic strategies in the treatment of IBD.
Highlights
Inflammatory bowel diseases (IBD) are idiopathic chronic, recurrent intestinal disorders of complex pathogenesis, which include Crohn’s disease (CD) and (UC) [1]
In the context of experimental colitis, central activation of the cholinergic anti-inflammatory pathway (CAP) by an M1mAChR agonist alters T cell priming via splenic dendritic cells (DCs), through an effect mediated by the vagus and the splenic nerve and the release of DC cytokine
First we examined the relation between the central stimulation and the development of experimental colitis
Summary
Inflammatory bowel diseases (IBD) are idiopathic chronic, recurrent intestinal disorders of complex pathogenesis, which include Crohn’s disease (CD) and (UC) [1]. Increased vagus nerve activity through the release of acetylcholine (ACh) in the reticuloendothelial system has been associated with decreased immune cell activation and altered cytokine release [9,10] This effect is mainly mediated through the alpha-7 nicotinic acetylcholine receptor (a7nAChR) signaling in antigen presenting cells [11]. We have previously reported that the central activation of the CAP inhibits acute inflammation in a murine models of colitis resembling UC and CD [9] In this context, treatments with galantamine ameliorated acute colitis through a dendritic cell (DC)-mediated mechanism and major histocompatibility complex (MHC) II regulation. The cholinergic anti-inflammatory pathway (CAP) is based on vagus nerve (VN) activity that regulates macrophage and dendritic cell responses in the spleen through alpha-7 nicotinic acetylcholine receptor (a7nAChR) signaling. The aim of this study was to investigate whether central activation of the CAP alters the function of dendritic cells (DCs) and sequential CD4+/CD252T cell activation in the context of experimental colitis
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