Neuronally released sympathetic neurotransmitters stimulate splenic interferon‐γ secretion from T cells in early type II collagen–induced arthritis

Abstract

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-␥ (IFN␥) 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␥ 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␥ 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␥ and KC. Electrical-field stimulation of the spleen slices reduced the secretion of IFN␥, which was attenuated by an ␣ 1 -adrenergic antagonist. In addition, splenic IFN␥ secretion was stimulated by norepinephrine, via ␤-adrenergic receptors, and adenosine, via A 1 adenosine receptors. Similarly, splenic KC secretion was stimulated by norepinephrine, via ␤-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␥ and KC, which, at the early stages shortly after the onset of CIA, can contribute to the proinflammatory effect of the sympathetic nervous system.

Restoring the Balance of the Autonomic Nervous System as an Innovative Approach to the Treatment of Rheumatoid Arthritis

“…Interestingly, the distribution and density of sympathetic nerves in lymphoid organs are not stable, but appear to change in response to alterations in the microenvironment, including immune activation and changes in cytokine release (12)(13)(14). The immune system is thereby capable of influencing the SNS and the innervation of lymphoid organs allows the SNS to influence the immune cells directly, via released NE which binds to ARs on these cells.…”

“…injections with 6-hydroxydopamine (6-OHDA) at different time points (35) (see also Table 1). The transition phase from pro-to antiinflammatory effects by the SNS is thought to lie between day 30 and day 55 after immunization in murine CIA (14,35). It has been suggested that the early, proinflammatory effects are caused by SNS-induced redistribution, migration and chemotaxis of leukocytes toward the site of inflammation (30,35 T cells from the sympathectomized CIA mice also displayed a reduced cytokine response (36).…”

“…In addition, an overall reduction of sympathetic nerve fibers was found in the spleen of DBA/1 mice with early, symptomatic CIA compared with normal DBA/1 mice. Despite this reduction, the SNS was still able to stimulate interferon-γ and cytokine-induced neutrophil chemoattractant-1 (CXCL-1) secretion by splenic T cells via various neurotransmitter systems (14). This demonstrates that the SNS can still contribute to diseaseaggravating effects in the early phase of arthritis despite reduced fiber density (14).…”

“…Despite this reduction, the SNS was still able to stimulate interferon-γ and cytokine-induced neutrophil chemoattractant-1 (CXCL-1) secretion by splenic T cells via various neurotransmitter systems (14). This demonstrates that the SNS can still contribute to diseaseaggravating effects in the early phase of arthritis despite reduced fiber density (14). As far as we are aware, there are no data on altered sympathetic innervation density of the spleen in RA patients.…”

Purinergic signalling in the musculoskeletal system

“…Sympathetic nerves have proinflammatory effects during the early phase of type II collagen-induced arthritis, probably mediated by cytokines, such as interferon-γ released by cells in response to sympathetic cotransmitters [395], and perhaps involving ATP. An important study supported the notion that α,β-meATP-sensitive P2X (probably P2X3) receptors are present in peripheral nociceptive afferent fibres in the rat knee joint and ATP, levels of which are increased in inflamed and damaged tissues, may be involved in the initiation of nociception and pain [396].…”