Activation of cutaneous immune responses in complex regional pain syndrome

J Pain. 2014 May;15(5):485-95. doi: 10.1016/j.jpain.2014.01.490. Epub 2014 Jan 23.


The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are elevated in experimental skin blister fluid from CRPS-affected limbs, as is tryptase, a marker for mast cells. In the rat fracture model of CRPS, exaggerated sensory and sympathetic neural signaling stimulate keratinocyte and mast cell proliferation, causing the local production of high levels of inflammatory cytokines leading to pain behavior. The current investigation used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation occur in CRPS skin and to identify the cellular source of the up-regulated TNF-α, IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies were collected from the affected skin and the contralateral mirror site in 55 CRPS patients and the biopsy sections were immunostained for keratinocyte, cell proliferation, mast cell markers, TNF-α, and IL-6. In early CRPS, keratinocytes were activated in the affected skin, resulting in proliferation, epidermal thickening, and up-regulated TNF-α and IL-6 expression. In chronic CRPS, there was reduced keratinocyte proliferation, leading to epidermal thinning in the affected skin. Acute CRPS patients also had increased mast cell accumulation in the affected skin, but there was no increase in mast cell numbers in chronic CRPS.

Perspective: The results of this study support the hypotheses that CRPS involves activation of the innate immune system, with keratinocyte and mast cell activation and proliferation, inflammatory mediator release, and pain.

Keywords: Complex regional pain syndrome; immunology; keratinocytes; mast cells; pain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Biopsy
  • Cell Proliferation
  • Complex Regional Pain Syndromes / pathology
  • Complex Regional Pain Syndromes / physiopathology*
  • Epidermis / immunology
  • Epidermis / pathology
  • Epidermis / physiopathology
  • Female
  • Humans
  • Interleukin-6 / metabolism
  • Keratinocytes / physiology
  • Male
  • Mast Cells / pathology
  • Mast Cells / physiology
  • Middle Aged
  • Organ Size
  • Skin / immunology*
  • Skin / pathology
  • Skin Physiological Phenomena*
  • Tumor Necrosis Factor-alpha / metabolism
  • Young Adult


  • IL6 protein, human
  • Interleukin-6
  • Tumor Necrosis Factor-alpha