Altered Sympathetic-to-Immune Cell Signaling via β (2)-Adrenergic Receptors in Adjuvant Arthritis

Adjuvant-induced arthritic (AA) differentially affects norepinephrine concentrations in immune organs, and in vivo β-adrenergic receptor (β-AR) agonist treatment distinctly regulates ex vivo cytokine profiles in different immune organs. We examined the contribution of altered β-AR functioning in AA to understand these disparate findings. Twenty-one or 28 days after disease induction, we examined β (2)-AR expression in spleen and draining lymph nodes (DLNs) for the arthritic limbs using radioligand binding and western blots and splenocyte β-AR-stimulated cAMP production using enzyme-linked immunoassay (EIA). During severe disease, β-AR agonists failed to induce splenocyte cAMP production, and β-AR affinity and density declined, indicating receptor desensitization and downregulation. Splenocyte β (2)-AR phosphorylation (pβ (2)-AR) by protein kinase A (pβ (2)-AR(PKA)) decreased in severe disease, and pβ (2)-AR by G protein-coupled receptor kinases (pβ (2)-AR(GRK)) increased in chronic disease. Conversely, in DLN cells, pβ (2)-AR(PKA) rose during severe disease, but fell during chronic disease, and pβ (2)-AR(GRK) increased during both disease stages. A similar pβ (2)-AR pattern in DLN cells with the mycobacterial cell wall component of complete Freund's adjuvant suggests that pattern recognition receptors (i.e., toll-like receptors) are important for DLN pβ (2)-AR patterns. Collectively, our findings indicate lymphoid organ- and disease stage-specific sympathetic dysregulation, possibly explaining immune compartment-specific differences in β (2)-AR-mediated regulation of cytokine production in AA and rheumatoid arthritis.