Neuronally Released Sympathetic Neurotransmitters Stimulate Splenic Interferon-γ Secretion From T Cells in Early Type II Collagen-Induced Arthritis

Objective. The sympathetic nervous system confers a proinflammatory effect during the early phase of type II collagen-induced arthritis (CIA). These effects might be mediated by up-regulation of cytokines such as interferon-gamma (IFN gamma) or chemokines such as CXCL1 (cytokine-induced neutrophil chemoattractant, or KC). This study aimed to identify the role of sympathetic neurotransmitters in splenic secretion of IFN gamma and KC shortly after the onset of CIA. Methods. At different time points during CIA, we determined the density of sympathetic nerve fibers in the spleens of mice. Spleens were removed when the mouse joints were assessed an arthritis score of 3 (at approximately day 32). Spleen slices (0.35 mm thick) were transferred to superfusion microchambers to allow observation of the effects of physiologically released sympathetic neurotransmitters on secretion of IFN gamma and KC. Results. Compared with control mice, mice with CIA demonstrated a decrease in sympathetic nerve fiber density in the spleens, which reached a minimum density shortly after the start of symptomatic arthritis (day 32). T cell depletion markedly reduced splenic secretion of IFN gamma and KC. Electrical-field stimulation of the spleen slices reduced the secretion of IFN gamma, which was attenuated by an alpha 1-adrenergic antagonist. In addition, splenic IFN gamma secretion was stimulated by norepinephrine, via beta-adrenergic receptors, and adenosine, via A, adenosine receptors. Similarly, splenic KC secretion was stimulated by norepinephrine, via beta-adrenergic receptors. Conclusion. The results of this study demonstrate a reduction of sympathetic nerve fibers in the spleens of arthritic animals. Nevertheless, sympathetic nerves help to increase secretion of IFN gamma and KC, which, at the early stages shortly after the onset of CIA, can contribute to the proinflammatory effect of the sympathetic nervous system.