gms | German Medical Science

Introduction: Density of sympathetic nerve fibers decreases in inflamed arthritic tissue tested by immunoreactivity towards tyrosine-hydroxylase (TH, catecholaminergic key enzyme). Since sympathetic nerve fibers can change phenotype from catecholaminergic to cholinergic (example: sweat glands, periosteum), an observed loss of sympathetic nerve fibers may relate to undetectable TH. We aimed to investigate possible catecholaminergic-to-cholinergic transition of sympathetic nerve fibers in synovial tissue of animals with arthritis, and patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and we wanted to find a possible transition factor.

Methods: Nerve fibers were detected by immunofluorescence towards TH (catecholaminergic) and vesicular acetylcholine transporter (VAChT, cholinergic). Co-culture experiments with sympathetic ganglia and lymphocytes or osteoclast progenitors were designed to find stimulators of catecholaminergic-to-cholinergic transition (including gene expression and proteome profiling).

Results: In mouse joints, an increased density of cholinergic relative to catecholaminergic nerve fibers appeared towards day 35 after immunization, but most cholinergic nerve fibers were located in healthy joint-adjacent skin or muscle and almost none in inflamed synovial tissue. In humans, cholinergic fibers are more prevalent in OA synovial tissue than in RA. Co-culture of sympathetic ganglia with osteoclast progenitors (OCPs) obtained from healthy but not from arthritic animals induced catecholaminergic-to-cholinergic transition. Osteoclast mRNA microarray data indicated that leukemia inhibitory factor (LIF) is a candidate transition factor in this setup, which was confirmed in ganglia experiments, particularly, in the presence of progesterone. Additionally, extracellular matrix related genes, oncostatin M (OSM, a known transition factor) and tissue inhibitor of metalloproteinase 1 (TIMP-1) protein were elevated in OCPs from healthy mice. In OCPs from arthritic mice, chemokine genes typical for macrophages and CCL5 (chemokine C-C motif ligand 5) protein were upregulated.

Conclusion: In humans and mice, catecholaminergic-to-cholinergic sympathetic transition happens in less inflamed tissue but not in inflamed arthritic tissue. Under healthy conditions, presence of cholinergic sympathetic nerve fibers may support the cholinergic anti-inflammatory influence recently described.