“Taming the Flame” in Autoimmune Arthritis: Reining in Sympathetic Nerve Activity Improves Disease Outcome and Shifts Pro/Anti‐inflammatory Cytokine Balance Uniquely in Relevant Immune Organs
Authors: Bellinger Denise Lorton , Lubahn Cheri L. , Lorton Dianne 
Published: November 2023

A myriad of factors conspire to obscure the etiology of autoimmunity, such as cytokines, hormones, neurotransmitters, environment and genetics. Thus, the trigger of disease onset remains perplexing. Since up to 80% of patients experience severe life stressors prior to the onset of an autoimmune disease in retrospective studies, including rheumatoid arthritis (RA), physical, and psychological stressors are strongly implicated in triggering the onset of disease. Moreover, autoimmunity itself creates significant stress in patients, providing a possible role for pathways that mediate physiologic responses to stressors in driving disease onset and progression. Still, evidence‐based research remains limited to support this hypothesis. To narrow this gap, we examined the role of high sympathetic nerve activity in the onset of RA using the adjuvant‐induced (AA) arthritis in Lewis rats as a model. We tested the hypothesis that lower sympathetic nerve activity (tone) after disease onset will ameliorate disease and shift inflammatory cytokines toward an anti‐inflammatory profile in relevant immune organs.Rats were immunized with complete Freund's adjuvant (CFA) to induce AA or components of CFA or saline. Moxonidine (MOX), an imidazoline receptor‐1 agonist that acts centrally to reduce SNS tone was used to lower sympathetic nerve activity in immune organs. Rats received vehicle or MOX (2 mg/kg/day; i.p. injection). Disease outcome was assessed using dorsoplantar widths and X‐ray analysis. Cytokines critical for inflammation and Th cell development were assessed by enzyme‐linked immunoassays in four immune organs: the spleen, joint‐draining and mesenteric draining lymph node (DLN and MLN, respectively) and peripheral blood mononuclear cells (PBMCs). Tested cytokines included interleukin (IL)‐1β, IL‐10, tumor necrosis factor (TNF)‐alpha, IL‐6, IL‐2, IL‐4, IFN‐gamma, and tumor growth factor (TGF)‐beta.Treatment with MOX dramatically reduced hind foot inflammation and joint destruction in AA compared with vehicle treatment. MOX treatment significantly reduced IL‐1beta, IL‐2, IL‐4 and IFN‐gamma in PBMCs. MOX treatment lowered splenocyte production of TGF‐beta and IFN‐gamma by ~50% and ~30, respectively. In contrast, MOX treatment had no effect on cytokine production in DLN cells, possibly due to different central centers regulating SNS activity in the DLN than in the spleen, with the former unaffected by MOX. Our findings support that suppressing sympathetic activity effectively reduced clinical signs of disease and altered the production of inflammatory cytokines uniquely in each immune tissue, particularly in the spleen. Our findings also support that MOX induced a shift in the balance between auto‐reactive Th cells and T regulatory cells in directions consistent with reduced disease activity. Given that the spleen is largely involved in systemic and the DLN in tissue immunity, our results may indicate a greater effect of lowering SNS tone on systemic disease rather than tissue immunity in the arthritic joints.Support or Funding InformationNIH Grant R29 MH49050