Targeting α- and β-Adrenergic Receptors Differentially Shifts Th1, Th2, and Inflammatory Cytokine Profiles in Immune Organs to Attenuate Adjuvant Arthritis

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.

Local cryotherapy improves adjuvant-induced arthritis through down-regulation of IL-6 / IL-17 pathway but independently of TNFα

“…Indeed, ice-water swimming was shown to increase peripheral norepinephrine levels in healthy subjects [ 16 ]. Furthermore, the α/β2-adrenergic receptor balance in the immune system has been shown to influence local and systemic inflammation as well as Th-1/Th-2 balance in AIA [ 57 ]. These systemic anti-inflammatory effects might also be partly related to NF-kB pathway inhibition in the spinal cord, which showed anti-inflammatory properties in AIA [ 58 ].…”

Molecular Mechanisms Underlying β-Adrenergic Receptor-Mediated Cross-Talk between Sympathetic Neurons and Immune Cells

“…Recent findings from our laboratory provide evidence for a shift in β 2 -AR signaling from cAMP to MAPK pathways in lymphocytes from rats with AA, a model of RA [ 46 , 133 ]. In these studies, β 2 -AR agonist treatment was started at disease onset and continued until severe disease.…”

“…Mesenteric lymph nodes (MLNs) were examined as a site where T lymphocytes that do not transfer the disease to naïve animals reside. Interestingly, arthritic animals treated with the β 2 -AR agonist, terbutaline altered IFN-γ production differently in each lymphoid organ examined, increasing IFN-γ in DLN cells, having no effect on IFN-γ in splenocytes, and inhibiting IFN-γ in MLN cells [ 133 ]. Reduced IFN-γ concentrations in MLN cells is consistent with the well-known ability of β 2 -AR stimulation to reduce IFN-γ production by increasing cAMP levels.…”

Leukocyte-Expressed β 2 -Adrenergic Receptors Are Essential for Survival After Acute Myocardial Injury

“…β2AR is the most highly and widely expressed βAR isoform 10, 14 , with a similar level of immune cell expression in rodents and humans 10, 14 , and is known to regulate a number of functions including hematopoiesis, lymphocyte homing and immune cell maturation 10 . However, the focus of many of these studies involved the effect of β2AR on adaptive immune responses, while its involvement in mediating early, innate immune responses and initiation of inflammation remains unclear 10, 15, 16 . β3AR has been shown to be important in early stages of hematopoiesis for mediating immune cell mobilization and egress from the bone marrow 17-19 .…”