Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Role of the Central Nervous System (CNS) in Peripheral Inflammation: Sympathetic Innervation of the Spleen Regulates Inflammatory Arthritis.
Boyle1, David L., Edgar2, Meghan, Sorkin2, Linda, Firestein1, Gary S.
The CNS has been identified as a key regulator of peripheral inflammatory and immune responses, especially spinal reflexes and the vagus nerve. However, the sympathetic nervous system can also modulate inflammation in animal models of arthritis, with counter-balancing pro-inflammatory and anti-inflammatory effects at different times during the course of the model. The mechanism of sympathetic influence on immune regulation in arthritis is unknown. Because the spleen is a secondary lymphoid organ exclusively innervated by sympathetic fibers, we explored the role of splenic denervation on adjuvant arthritis in the rat.
Surgical splenic denervation of male Lewis rats was performed by dual transection and removal of the intervening segment of the splenic nerve and confirmed by norepinephrine assay of the spleen. Adjuvant arthritis was induced by injecting 1mg complete complete Freund's adjuvant at the base of the tail. Arthritis severity was measured by hind-limb plethysmometry. Hind-limb radiographs were scored on a 06 point scale. Splenic mRNA expression was determined by QPCR and expressed as relative expression units (REU).
Splenic denervation (SD) decreased paw swelling by 48% compared with controls (C) (SD 0.65±0.2ml versus C 1.34±0.1ml; p<0.0001). Radiographic analysis showed that SD significantly decreased bone destruction (SD 1.1±0.4; C 2.20±0.2; p<0.03).
Splenic norepinephrine levels in C animals were 3.1±0.4ng/mg tissue at baseline (day 0) and trended to higher levels in active arthritis (day 12, 4.8±1.1ng/mg), and decreased to below baseline levels at the end of the model (day 21, 0.9±0.1ng/mg; p<0.0001 compared to baseline). Denervation reduced splenic norepinephrine to 0.48±0.34 ng/mg at all time points. TNF expression in arthritic animals was also reduced in denervated spleens (0.258±0.03 REU in SD vs 0.48±0.12 REU in SH; p<0.02). IL-1, GRO/CINQ1, IFNg, IL-2 and TGF-b were not affected. Spleen mass was indistinguishable between SD and C groups in the presence or absence of arthritis, although spleen mass was doubled in arthritic animals compared with non-arthritic.
The sympathetic nervous system regulates the immune response in acute and chronic inflammation. Surprisingly, sympathetic innervation of the spleen is a key mechanism for neuro-regulation of inflammatory arthritis and is required for full expression of synovitis and matrix destruction. The mechanisms might include direct effects of neurotransmitters on immune cells via b adrenergic receptors, such as macrophages, with reduced splenic TNF production.
To cite this abstract, please use the following information:
Boyle, David L., Edgar, Meghan, Sorkin, Linda, Firestein, Gary S.; Role of the Central Nervous System (CNS) in Peripheral Inflammation: Sympathetic Innervation of the Spleen Regulates Inflammatory Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1727