Abstract
The sympathetic nervous system (SNS) regulates host defense responses and restores homeostasis. SNS-immune regulation is altered in rheumatoid arthritis (RA) and rodent models of RA, characterized by nerve remodeling in immune organs and defective adrenergic receptor (AR) signaling to immune cell targets. The SNS typically promotes or suppresses inflammation via α- and β2-AR activation, respectively, and indirectly drives humoral immunity by blocking Th1 cytokine secretion. Here, we investigate how β2-AR stimulation and/or α-AR blockade at disease onset affects disease pathology and cytokine profiles in relevant immune organs from male Lewis rats with adjuvant-induced arthritis (AA). Rats challenged to induce AA were treated with terbutaline (TERB), a β2-AR agonist (600 μg/kg/day) and/or phentolamine (PHEN), an α-AR antagonist (5.0 mg/kg/day) or vehicle from disease onset through severe disease. We report that in spleen, mesenteric (MLN) and draining lymph node (DLN) cells, TERB reduces proliferation, an effect independent of IL-2. TERB also fails to shift T helper (Th) cytokines from a Th1 to Th2 profile in spleen and MLN (no effect on IFN-γ) and DLN (greater IFN-γ) cells. In splenocytes, TERB, PHEN, and co-treatment (PT) promotes an anti-inflammatory profile (greater IL-10) and lowers TNF-α (PT only). In DLN cells, drug treatments do not affect inflammatory profiles, except PT, which raised IL-10. In MLN cells, TERB or PHEN lowers MLN cell secretion of TNF-α or IL-10, respectively. Collectively, our findings indicate disrupted β2-AR, but not α-AR signaling in AA. Aberrant β2-AR signaling consequently derails the sympathetic regulation of lymphocyte expansion, Th cell differentiation, and inflammation in the spleen, DLNs and MLs that is required for immune system homeostasis. Importantly, this study provides potential mechanisms through which reestablished balance between α- and β2-AR function in the immune system ameliorates inflammation and joint destruction in AA.
Highlights
Autonomic and immune dysfunction, and dysregulation of their cross-communication in autoimmune diseases, are hallmarks of many autoimmune diseases, including rheumatoid arthritis (RA) [1,2,3,4]
There was a dramatic reduction in the radiographic scores from the arthritic rats treated with TERB compared with VEH-treated arthritic rats (Figure 1B; pTERB < 0.05, pPHEN < 0.05, or pPT < 0.01)
Consistent with previous findings, TERB, PHEN, or PT dramatically ameliorates adjuvant-induced arthritis (AA) in male Lewis rats when treatment begins at disease onset [12]
Summary
Dysregulation of their cross-communication in autoimmune diseases, are hallmarks of many autoimmune diseases, including rheumatoid arthritis (RA) [1,2,3,4]. Altered innate and adaptive immunity are key mediators of the disease process [5, 6]. Dysregulation of the SNS in the immune system contributes significantly to disease onset, and greater severity in RA and experimentally-induced arthritis [7, 8]. The contribution of a dysregulated SNS and the altered cross-communication between SNS and the immune system in autoimmune diseases is complex. We still do not understand the complex and diverse roles of the SNS in regulating innate and adaptive immunity that mediate rheumatic disease mechanisms prior to and after disease onset. Growing evidence indicates that the SNS is an important target for developing disease amelioration, or even preventing disease onset, supporting the need to understand sympathetic-immune system cross-talk in RA [2]
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