Pathways of the cholinergic anti-inflammatory reflex in arthritis

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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.