An Opposing Time-Dependent Immune-Modulating Effect of the Sympathetic Nervous System Conferred by Altering the Cytokine Profile in the Local Lymph Nodes and Spleen of Mice With Type II Collagen-Induced Arthritis

Arthritis Rheum. 2005 Apr;52(4):1305-13. doi: 10.1002/art.20987.


Objective: The sympathetic nervous system (SNS) seems to play a proinflammatory role in the early asymptomatic phase of arthritis, but its role in the late stages of chronic arthritis is not well known. The purpose of this study was to examine the effects of the SNS on late-stage chronic arthritis in mice with type II collagen-induced arthritis (CIA).

Methods: We tested the effects of the SNS by ablating sympathetic nerves at different time points in mice with CIA. Early sympathectomy was performed 7 days before immunization. Late sympathectomy was performed on day 56. Cytokine stimulation assays were performed on local lymph node cells and spleen cells, and levels of interleukin-10 (IL-10), IL-4, tumor necrosis factor alpha (TNFalpha), and interferon-gamma (IFNgamma) were determined.

Results: Animals with CIA that underwent early sympathectomy showed significantly lower arthritis scores than the controls. In contrast, animals that underwent late sympathectomy had significantly increased arthritis scores compared with controls. On day 0, lymph node cells from animals subjected to early sympathectomy had increased levels of IL-10 and IL-4 and unchanged levels of TNFalpha and IFNgamma compared with those from untreated animals. This indicates an immune-stimulating property of the SNS in draining lymph nodes. On day 80, lymph node cells and spleen cells from animals subjected to late sympathectomy showed increased levels of TNFalpha and IFNgamma compared with those from nonsympathectomized controls with CIA. This indicates an immune-depressing property of the SNS in draining lymph nodes and spleen. Arthritis per se largely diminished sympathetic nerve fiber density in synovium on day 80 (P < 0.01).

Conclusion: The effect of the SNS is bimodal, enhancing or depressing levels of proinflammatory and antiinflammatory cytokines. This feature is dependent on the time point of immune system activation and the respective compartment. The SNS supports inflammation during the asymptomatic phase of CIA, whereas it inhibits inflammation during the chronic symptomatic phase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / pathology
  • Chemotaxis, Leukocyte / immunology
  • Collagen Type II / immunology
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Female
  • Joints / innervation
  • Joints / pathology
  • Lymph Nodes / immunology*
  • Lymph Nodes / metabolism
  • Mice
  • Mice, Inbred DBA
  • Spleen / immunology*
  • Spleen / metabolism
  • Sympathectomy, Chemical
  • Sympathetic Nervous System / immunology*
  • Sympathetic Nervous System / pathology
  • Synovial Membrane / innervation
  • Synovial Membrane / pathology
  • Time Factors


  • Collagen Type II
  • Cytokines