Vagotomy Affects the Development of Oral Tolerance and Increases Susceptibility to Develop Colitis Independently of α-7 Nicotinic Receptor

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. online address: http://www.molmed.org

The Vagus Nerve in Appetite Regulation, Mood, and Intestinal Inflammation

“…Preclinical models provide convincing evidence that the cholinergic innervation of the gut has a major impact on the intestinal immune system. As indicated above, vagotomized animals fail to develop oral tolerance 98 and develop more severe colitis with increased levels of NF-kB and cytokines in DSS and hapten-induced (dinitrobenzene sulfonic acid or DNBS) colitis 98,105,106 . Similarly, mice with depressive-like behavior following chronic reserpine treatment, which is associated with reduced intestinal levels of acetylcholine, developed more severe DSS and DNBS-induced colitis 107 .…”

“…Of interest, treatment with the anti-depressant desimipramine reversed these effects in a vagus-dependent manner. In contrast, vagotomy does not affect T cell transfer-induced colitis 98,108 , indicating that T cells are less likely to be under direct vagal/cholinergic control. Macrophages or dendritic cells may be more likely to be involved; vagotomy had no effect on colitis in macrophage deficient mice 105 , while adoptive transfer of macrophages isolated from vagotomized mice or mice treated with reserpine to macrophage-deficient M-CSF-/- mice produced a modest, but significant, increase in severity of colitis 109 .…”

“…One of the key mechanisms for discrimination of innocent and harmful antigens is oral tolerance, a mechanism orchestrated by the mucosal immune system and dependent on FoxP3+ regulatory T cells (Tregs). We showed recently that vagotomy reduced the ability to develop oral tolerance, a finding that was associated with a reduction in Tregs in the lamina propria and mesenteric lymph nodes 98 . Of note, vagotomized mice were more susceptible to developing colitis following exposure to the mucosal irritant, dextran sulfate sodium (DSS), suggesting that, in addition to TGF-β, retinoic acid and TSLP 99 , vagal input, or cholinergic tone, may be a new player in determining the degree of lamina propria tolerance (Figure 2).…”

“…Their role in colitis, however, is somewhat controversial. We showed recently the intact development of oral tolerance and lack of increased susceptibility for development of DSS-induced or T cell transfer colitis in α7nAChR−/− mice 98 , while DSS colitis was worsened by treatment with selective α7nAChRs agonists (AR-R17779, GSK1345038A) 116 . Conversely, others reported more severe DSS-induced colitis and increased IL-1b and IL-6 levels in colonic tissue of α7nAChR−/− mice 110 while cytokine production of splenocytes and splenic CD11c+ cells isolated from colitis mice is reduced by the α7nAChR agonist GTS-21.…”

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis

“…The balance of the ANS can be measured via assessment of heart rate variability (HRV), whereby in rest HRV is decreased if the parasympathetic influence on the heart is reduced. mice did not exhibit increased colitis activity and treatment with the specific a7nAChR-agonist (AR-R17779 or GSK1345038A) was associated with worsening of the disease [68,69].…”