Altered sympathetic-to-immune cell signaling via β₂-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 β₂-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 β₂-AR phosphorylation (pβ₂-AR) by protein kinase A (pβ₂-AR(PKA)) decreased in severe disease, and pβ₂-AR by G protein-coupled receptor kinases (pβ₂-AR(GRK)) increased in chronic disease. Conversely, in DLN cells, pβ₂-AR(PKA) rose during severe disease, but fell during chronic disease, and pβ₂-AR(GRK) increased during both disease stages. A similar pβ₂-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 pβ₂-AR patterns. Collectively, our findings indicate lymphoid organ- and disease stage-specific sympathetic dysregulation, possibly explaining immune compartment-specific differences in β₂-AR-mediated regulation of cytokine production in AA and rheumatoid arthritis.