Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis synovium and aggravates sympathetic fiber repulsion and arthritis

Abstract

Objective: In inflammatory lesions, sympathetic nerve fibers disappear soon after the start of inflammation. We identified sympathetic nerve repellents as possible causal agents in rheumatoid arthritis (RA). On nerve terminals, repellent factors bind to neuropilin-2 and its coreceptor. The aim of this study was to investigate the role of neuropilin-2 in the synovial tissue of patients with RA and patients with osteoarthritis (OA) and in experimental arthritis.

Methods: The density of neuropilin-2-positive fibers and cells positive for semaphorin 3F (a sympathetic repellent) was investigated using immunofluorescence staining. Enzyme-linked immunosorbent assay was used to detect soluble neuropilin-2 in body fluids from patients with RA and patients with OA. An axon outgrowth assay and a neuropilin-2 Fc fusion construct (neuropilin-2Fc) were used to investigate semaphorin 3F-induced sympathetic nerve repulsion. In an animal model of type II collagen-induced arthritis, soluble neuropilin-2Fc was studied in vivo.

Results: The synovial density of neuropilin-2-positive sympathetic nerve fibers was lower in RA than in OA, but the density of cells positive for semaphorin 3F was similar. In synovial fluid, the level of soluble neuropilin-2 was markedly higher in RA compared with OA. Mouse sympathetic ganglia served as an excellent model with which to study semaphorin 3F-induced nerve fiber repulsion. Neuropilin-2 and its coreceptor were present on sympathetic neurons, and semaphorin 3F bound to neuropilin-2Fc (binding constant 96 nmoles/liter). Semaphorin 3F dose-dependently increased sympathetic nerve fiber repulsion (at a 50% maximum response concentration of 160-210 nmoles/liter). In contrast to our expectations, soluble neuropilin-2Fc did not inhibit repulsion but increased the repellent effect of semaphorin 3F. In experimental arthritis, therapy with neuropilin-2Fc aggravated arthritis.

Conclusion: Soluble neuropilin-2 has no antirepellent activity but aggravates sympathetic nerve fiber repulsion and arthritis. Increased shedding of neuropilin-2 is probably an unfavorable sign in RA.