An early sympathetic nervous system influence exacerbates collagen‐induced arthritis via CD4+CD25+ cells

Abstract

Objective. Activation of the sympathetic nervous system (SNS) ameliorates collagen-induced arthritis (CIA) in the late phase of the disease but aggravates it in the presymptomatic phase. The aim of the present study was to determine whether CD4؉CD25؉ T cells are influenced by the SNS of mice and play a diseasemodifying role in the early symptomatic phase of the disease.Methods. We tested the effects of the SNS on arthritis by transferring CD4؉CD25؉ T cells from sympathectomized mice immunized with type II collagen and from immunized, SNS-intact animals (controls). We further characterized transferred cells by studying forkhead box P3 (FoxP3) expression, cell proliferation, and cytokine secretion.Results. Using anti-dopamine-␤-hydroxylase antibodies for systemic sympathectomy, we noticed a timedependent disease amelioration (strongest when sympathectomy was performed 7 days before immunization, with no effect 30 days after immunization). When CD4؉CD25؉ T cells from immunized and sympathectomized animals were transferred into mice with CIA (on day 32), disease severity was reduced compared with that in controls. However, the number of CD4؉CD25؉FoxP3؉ cells and the FoxP3 expression level in CD4؉CD25؉ cells were not changed by sympathectomy. In a mixed assay of donor CD4؉CD25؊ and CD4؉CD25؉ cells, proliferation was reduced when cells from sympathectomized animals were studied. In the same assay, secretion of tumor necrosis factor, interleukin-17 (IL-17), IL-10, and IL-4 (not interferon-␥) was markedly reduced when cells were taken from sympathectomized animals. Culture of CD4؉CD25؉ cells with norepinephrine (10 ؊5 M) for 24 hours before transfer worsened the arthritis.Conclusion. The SNS increases disease severity in the early phase of symptomatic CIA by stimulating several proinflammatory aspects of CD4؉CD25؉ T cells.

The anti-inflammatory effects of sympathectomy in murine antigen-induced arthritis are associated with a reduction of Th1 and Th17 responses

“…In particular, IL-17 has a major proinflammatory role in primary and flare-up reactions of AIA, whereas IFNγ has a pronounced pro- and anti-inflammatory role in both AIA and CIA 9 23–26. Furthermore, sympathectomy modulated the number and activity of regulatory T cells in CIA and autoimmune encephalomyelitis 27 28…”

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

“…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). β2-Adrenergic receptor agonists or antagonists in experimental arthritis.…”

The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease

“…The influence of adrenergic signaling and the loss of sympathetic nerve fibers in the inflamed tissue in RA has been demonstrated in several animal models of arthritis (68). Sympathectomy in the early phase of the disease has been shown to ameliorate experimental arthritis, indicating the pro-inflammatory influence of adrenergic signaling (69). During arthritic inflammation, nerve repulsion factors released by macrophages result in the withdrawal of sympathetic neurons from the synovial tissue and the subsequent depletion of synovial norepinephrine concentrations (68).…”