Abstract
Vagotomy (VGX) increases the susceptibility to develop colitis suggesting a crucial role for the cholinergic anti-inflammatory pathway in the regulation of the immune responses. Since oral tolerance and the generation of regulatory T cells (Tregs) are crucial to preserve mucosal immune homeostasis, we studied the effect of vagotomy and the involvement of α7 nicotinic receptors (α7nAChR) at the steady state and during colitis. Therefore, the development of both oral tolerance and colitis (induced by dextran sulfate sodium (DSS) or via T cell transfer) was studied in vagotomized mice and in α7nAChR-/- mice. VGX, but not α7nAChR deficiency, prevented oral tolerance establishment. This effect was associated with reduced Treg conversion in the lamina propria and mesenteric lymphnodes. To the same extent, vagotomized mice, but not α7nAChR-/- mice, developed a more severe DSS colitis compared with control mice treated with DSS, associated with a decreased number of colonic Tregs. However, neither VGX nor absence of α7nAChR in recipient mice affected colitis development in the T cell transfer model. In line, deficiency of α7nAChR exclusively in T cells did not influence the development of colitis induced by T cell transfer. Our results indicate a key role for the vagal intestinal innervation in the development of oral tolerance and colitis, most likely by modulating induction of Tregs independently of α7nAChR.
Highlights
Recent studies have undoubtedly demonstrated that the nervous system extensively interacts with the immune system to modulate systemic and peripheral inflammation [1]
In 2005, we extended this concept to the gastrointestinal (GI) tract showing that vagus nerve stimulation (VNS) reduced inflammation and restored GI transit in a murine model of postoperative ileus (POI) [5]
As Tregs are the main players in establishing oral tolerance, we evaluated the effect of VGX on the development of Tregs in the lamina propria and mesenteric lymph nodes (MLNs) via a T cell conversion assay (Figure 1C)
Summary
Recent studies have undoubtedly demonstrated that the nervous system extensively interacts with the immune system to modulate systemic and peripheral inflammation [1]. In 2000, Tracey and co-workers elegantly showed that vagus nerve stimulation (VNS) reduced proinflammatory cytokine release and increased survival in a model of sepsis [2]. This antiinflammatory effect, called cholinergic antiinflammatory pathway (CAIP), resulted in inhibition of splenic macrophages (Mφs) through the activation of alpha nicotinic acetylcholine receptors (α7nAChR) [3, 4]. In the context of POI, we recently demonstrated that VNS exerts its antiinflammatory effect in the intestinal muscularis externa by activating cholinergic enteric neurons in close contact with CX3CR1high α7nAChR+ resident Mφs [6]. We hypothesized that increased susceptibility to develop colitis following
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