Pathways of the cholinergic anti-inflammatory reflex in arthritis

自从胆碱能抗炎通路被发现以来，关于它在慢性关节炎中是否有价值存在着很大的争论。人们普遍认为α7亚单位烟碱能乙酰胆碱受体(Alpha7nAChR)在抗炎作用中起重要作用，因为alpha7nAChR激动剂对关节炎有益。在这个项目中，胆碱能途径的三个主要方面将被研究。1)慢性迷走神经电刺激(VNS)将在40天以上应用于关节炎大鼠，以确定受累的传出轴(α7nAChR拮抗剂[测试胆碱能通路]，或阻断下丘脑-垂体-肾上腺轴，或伴有交感神经系统抑制)。2)本课题组最近的研究表明，儿茶酚胺能交感神经纤维可以在白血病抑制因子和孕酮的作用下转化为胆碱能表型。在这个项目中，这个概念将被用来在大鼠身上部分改变交感神经纤维的表型，从而在II型胶原免疫前后诱导胆碱能环境。我们预计目标1)或目标2)或两者都在大鼠身上显示出有益的抗关节炎作用，但从这些体内研究中还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，第一部分或第二部分中最有益的抗关节炎策略将被用来测试从淋巴器官分离的调节性T细胞是否传递这些有利的效果。因此，患有关节炎的捐赠者将得到最有益的治疗，调节性T细胞将从捐赠者的脾中移除，这些细胞将被转移到关节炎受体。这将向我们展示影响的细胞路径。我们期待与胆碱能抗炎途径相关的重大新发现，这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.