Central sympathetic inhibition ameliorates joint pathology and shifts cytokines profiles in spleen but not joint draining lymph nodes in a model of rheumatoid arthritis

In 80% of patients, major life stressors precede onset of autoimmune diseases, including rheumatoid arthritis (RA) linking stress pathway activation to disease onset. We examined the contribution of high sympathetic nervous system activity to RA onset using the adjuvant-induced (AA) arthritis model in Lewis rats. Rats were immunized with complete Freund's adjuvant to induce AA. From day (D)12 (disease onset) through D28, rats were treated with vehicle or 2 mg/kg/day moxonidine, an imidazoline receptor-1 agonist that acts centrally to reduce SNS tone. Disease outcome was assessed using dorsoplantar widths and X-ray analysis. Cytokines critical for inflammation and CD4+ Th cell development (interleukin (IL)-1/?, IL-10, tumor necrosis factor (TNF)-a, IL-6, IL-2, IL-4, IFN-y, and tumor growth factor (TGF)-/?) were assessed in spleen, draining lymph node (DLN) and peripheral blood mononuclear cells (PBMCs) by enzyme-linked immunoassays. Treatment with moxonidine dramatically prevented hind foot inflammation and joint destruction in AA compared with vehicle treatment. In DLN cells, moxonidine treatment had no effect on cytokine production. In contrast, moxonidine treatment significantly reduced IL-1/?, IL-2, IL-4 and IFN-y in PBMCs. Drug treatment decreased splenocyte production of TGF-/? and IFN-y by ~50% and ~30%, respectively. Lowering SNS tone effectively reduced clinical signs of disease and altered production of cytokines involved in inflammation and shifting the balance between auto-reactive CD4+Th cells and T regulatory cells in directions expected to limit disease activity.