Pathways of the cholinergic anti-inflammatory reflex in arthritis

自从胆碱能抗炎通路被发现以来，对于它是否在慢性关节炎中有价值存在着很大的争议。公认的是，α 7亚基烟碱能乙酰胆碱受体（α 7 nAChR）有助于抗炎作用，因为α 7 nAChR激动剂在关节炎中是有益的。在这个项目中，三个主要方面的胆碱能途径将进行调查。1)将在关节炎大鼠中应用慢性迷走神经电刺激（VNS）超过40天，以表征所涉及的传出轴（α 7 nAChR拮抗剂[测试胆碱能通路]，或阻断下丘脑-垂体-肾上腺轴，或抑制交感神经系统）。2)本课题组最近的研究表明，儿茶酚胺能交感神经纤维可被白血病抑制因子和孕酮转化为胆碱能表型。在这个项目中，这一概念将被用于大鼠部分改变交感神经纤维的表型，从而诱导胆碱能环境之前和之后的免疫与II型胶原蛋白。我们预期目标1）或目标2）或两者在大鼠中显示出有益的抗关节炎作用，但这些体内研究不清楚负责的细胞类型。然而，我们预计调节性T细胞发挥主要作用。3)因此，第1部分或第2部分的最有益的抗关节炎策略将用于测试从淋巴器官分离的调节性T细胞是否转移这些有利的作用。因此，患有关节炎的供体将用最有益的策略进行治疗，调节性T细胞将从供体脾脏中去除，这些细胞将转移到关节炎受体中。这将向我们展示影响的细胞路径。我们期待与胆碱能抗炎通路相关的重大新发现，可能适合作为未来的治疗策略。

Since the discovery of the cholinergic anti-inflammatory pathway there was much debate whether it can be valuable in chronic arthritis. It is accepted that the alpha7 subunit nicotinergic acetylcholine receptor (alpha7nAChR) is instrumental in anti-inflammatory effects because alpha7nAChR agonists are beneficial in arthritis. In this project, three major aspects of the cholinergic pathway will be investigated. 1) Chronic electrical vagus nerve stimulation (VNS) will be applied over 40d in arthritic rats in order to characterize the involved efferent axis (alpha7nAChR antagonist [testing the cholinergic pathway], or with blockade of the hypothalamic-pituitary-adrenal axis, or with inhibition of the sympathetic nervous system). 2) Recent studies of our group demonstrated that catecholaminergic sympathetic nerve fibers can be converted to a cholinergic phenotype by leukemia inhibitory factor and progesterone. In this project, this concept will be used in rats to partly change the phenotype of sympathetic nerve fibers, thereby, inducing a cholinergic milieu before and after immunization with collagen type II. We expect that either goal 1) or goal 2) or both show beneficial, anti-arthritic effects in rats but the responsible cell type is not clear from these in vivo studies. However, we expect that regulatory T cells play a major role. 3) Thus, the most beneficial, anti-arthritic strategy of part 1 or part 2 will be used to test whether regulatory T cells separated from lymphoid organs - transfer these favorable effects. Hence, donors with arthritis will be treated with the most beneficial strategy, regulatory T cells will be removed from donor spleen, and these cells will be transferred to arthritic recipients. This will show us the cellular route of influence. We expect major new findings in relation to the cholinergic anti-inflammatory pathway that might be suitable as a future therapeutic strategy.