Altered Sympathetic-to-Immune Cell Signaling viaβ2-Adrenergic Receptors in Adjuvant Arthritis

Abstract

Adjuvant-induced arthritic (AA) differentially affects norepinephrine concentrations in immune organs, andin vivoβ-adrenergic receptor (β-AR) agonist treatment distinctly regulatesex vivocytokine profiles in different immune organs. We examined the contribution of alteredβ-AR functioning in AA to understand these disparate findings. Twenty-one or 28 days after disease induction, we examinedβ2-AR expression in spleen and draining lymph nodes (DLNs) for the arthritic limbs using radioligand binding and western blots and splenocyteβ-AR-stimulated cAMP production using enzyme-linked immunoassay (EIA). During severe disease,β-AR agonists failed to induce splenocyte cAMP production, andβ-AR affinity and density declined, indicating receptor desensitization and downregulation. Splenocyteβ2-AR phosphorylation (pβ2-AR) by protein kinase A (pβ2-ARPKA) decreased in severe disease, and pβ2-AR by G protein-coupled receptor kinases (pβ2-ARGRK) increased in chronic disease. Conversely, in DLN cells, pβ2-ARPKArose during severe disease, but fell during chronic disease, and pβ2-ARGRKincreased 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 inβ2-AR-mediated regulation of cytokine production in AA and rheumatoid arthritis.