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

Abstract

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-ARPKA) decreased in severe disease, and pβ 2-AR by G protein-coupled receptor kinases (pβ 2-ARGRK) increased in chronic disease. Conversely, in DLN cells, pβ 2-ARPKA rose during severe disease, but fell during chronic disease, and pβ 2-ARGRK 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.

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

“…Receptor desensitization, degradation and recycling are important for maintaining homeostasis and ensuring fine tuning of the response being modulated. Malfunction of the β 2 -AR desensitization process has been linked to various diseases, including heart failure [ 41 , 42 , 43 ], asthma [ 44 ], and autoimmune diseases [ 45 , 46 ].…”

How stress contributes to autoimmunity—lessons from Sjögren's syndrome

“…Thus, the ANS of these patients, following the irregular HPA response, may be in a constant imbalance, characterized by high sympathetic and low parasympathetic tone. This imbalance has also been described in patients with Rheumatoid Arthritis and may have deleterious effects on the target organs of the autoimmune arena, as are the glandular epithelial cells of exocrine glands in SS patients.…”

“…In both the organ‐specific and the systemic autoimmune diseases, at least in the beginning, the immune system shows a preference for a target tissue. There is growing evidence indicating that these tissues conceal in their cells the triggering factors against which the immune system reacts . The predominant perception is that viral infection of these cells may be the key factors for the autoimmune reactivity .…”

Immune Tolerance Effect in Mesenteric Lymph Node Lymphocytes of Geniposide on Adjuvant Arthritis Rats

“…The MLN lymphocyte is an important organization connecting local immunity and systemic immunity and is essential for immune tolerance (Van Esch et al ., ; Lorton et al ., ). External mucosal surfaces are filled with organized follicles and scattered antigen‐reactive or sensitized lymphoid elements involved in the induction and maintenance of immune response, including T lymphocytes, T cell subsets, B cells, plasma cells, and a variety of other cellular elements (Michael et al ., ; Moussa et al ., ).…”