Peripheral elimination of the sympathetic nervous system stimulates immunocyte retention in lymph nodes and ameliorates collagen type II arthritis

Brain Behav Immun. 2016 May;54:201-210. doi: 10.1016/j.bbi.2016.02.006. Epub 2016 Feb 9.


Objectives: In collagen type II-induced arthritis (CIA), early activation of the sympathetic nervous system (SNS) is proinflammatory. Here, we wanted to find new target organs contributing to proinflammatory SNS effects. In addition, we wanted to clarify the importance of SNS-modulated immunocyte migration.

Methods: A new technique termed spatial energy expenditure configuration (SEEC) was developed to demonstrate bodily areas of high energy demand (to find new targets). We studied homing of labeled cells in vivo, lymphocyte expression of CCR7, supernatant concentration of CCL21, and serum levels of sphingosine-1-phosphate (S1P) in sympathectomized control/arthritic animals.

Results: During the course of arthritis, SEEC identified an early marked increase of energy expenditure in draining lymph nodes and spleen (nowhere else!). Although early sympathectomy ameliorated later disease, early sympathectomy increased energy consumption, organ weight, and cell numbers in arthritic secondary lymphoid organs, possibly a sign of lymphocyte retention (also in controls). Elimination of the SNS retained lymph node cells, elevated expression of CCR7 on lymph node cells, and increased CCL21. Serum levels of S1P, an important factor for lymphocyte egress, were higher in arthritic than control animals. Sympathectomy decreased S1P levels in arthritic animals to control levels. Transfer of retained immune cells from draining lymph nodes of sympathectomized donors to sympathectomized recipients markedly increased arthritis severity over weeks.

Conclusions: By using the SEEC technique, we identified draining lymph nodes and spleen as major target organs of the SNS. The data show that the SNS increases egress of lymphocytes from draining lymph nodes to stimulate arthritic inflammation.

Keywords: Arthritis; Leukocyte egress; Leukocyte entry; Secondary lymphoid organ; Sympathetic nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / immunology*
  • Arthritis, Experimental / therapy*
  • Central Nervous System Stimulants
  • Collagen Type II / immunology*
  • Collagen Type II / metabolism
  • Cytokines / metabolism
  • Immune System / metabolism
  • Lymph Nodes / immunology*
  • Lymph Nodes / metabolism
  • Lymphocytes / metabolism
  • Male
  • Mice
  • Mice, Inbred DBA
  • Norepinephrine / metabolism
  • Spleen / metabolism
  • Sympathectomy, Chemical
  • Sympathetic Nervous System / immunology*
  • Sympathetic Nervous System / metabolism


  • Central Nervous System Stimulants
  • Collagen Type II
  • Cytokines
  • Norepinephrine