Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation

Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16451-6. doi: 10.1073/pnas.0908507106. Epub 2009 Sep 4.


Peripheral interactions between nociceptive fibers and mast cells contribute to inflammatory pain, but little is known about mechanisms mediating neuro-immune communication. Here we show that metalloproteinase MT5-MMP (MMP-24) is an essential mediator of peripheral thermal nociception and inflammatory hyperalgesia. We report that MT5-MMP is expressed by CGRP-containing peptidergic nociceptors in dorsal root ganglia and that Mmp24-deficient mice display enhanced sensitivity to noxious thermal stimuli under basal conditions. Consistently, mutant peptidergic sensory neurons hyperinnervate the skin, a phenotype that correlates with changes in the regulated cleavage of the cell-cell adhesion molecule N-cadherin. In contrast to basal nociception, Mmp24(-/-) mice do not develop thermal hyperalgesia during inflammation, a phenotype that appears associated with alterations in N-cadherin-mediated cell-cell interactions between mast cells and sensory fibers. Collectively, our findings demonstrate an essential role of MT5-MMP in the development of dermal neuro-immune synapses and suggest that this metalloproteinase may be a target for pain control.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • COS Cells
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Chlorocebus aethiops
  • Female
  • Fluorescent Antibody Technique
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / metabolism*
  • Hot Temperature
  • Humans
  • Hyperalgesia / genetics
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / physiopathology
  • Male
  • Matrix Metalloproteinases, Membrane-Associated / genetics
  • Matrix Metalloproteinases, Membrane-Associated / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Nociceptors / metabolism*
  • Peripheral Nervous System Diseases / genetics
  • Peripheral Nervous System Diseases / metabolism
  • Peripheral Nervous System Diseases / physiopathology
  • Transfection


  • Cadherins
  • Matrix Metalloproteinases, Membrane-Associated
  • Mmp24 protein, mouse