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Pathways of the cholinergic anti-inflammatory reflex in arthritis

关节炎中胆碱能抗炎反射的途径

基本信息

批准号：
278103889
负责人：
Professor Dr. Rainer H. Straub
金额：
--
依托单位：
Klinik und Poliklinik für Innere Medizin I
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/278103889?language=en
关键词：
Pathways cholinergic anti inflammatory reflex

项目摘要

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.

自发现胆碱能抗炎途径以来，对其在慢性关节炎中是否有价值一直存在争议。人们普遍认为，alpha7亚基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进行研究。1)慢性迷走神经电刺激（VNS）将在关节炎大鼠中应用超过40天，以表征受累的传出轴（alpha7nAChR拮抗剂[测试胆碱能途径]，或通过阻断下丘脑-垂体-肾上腺轴，或通过抑制交感神经系统）。2)本课题组近期研究表明，儿茶酚胺能交感神经纤维可通过白血病抑制因子和黄体酮转化为胆碱能表型。在这个项目中，这个概念将在大鼠身上使用，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。我们期望目标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尚不清楚负责的细胞类型。然而，我们期望调节性T细胞发挥主要作用。3)因此，第1部分或第2部分中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作用。因此，患有关节炎的供体将采用最有益的策略进行治疗，调节性T细胞将从供体脾脏中移除，并将这些细胞转移到患有关节炎的受者身上。这将向我们展示细胞的影响途径。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。