Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation.
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.
Folgueras
Alicia R
AR
Departamento de Bioquímica y Biología Molecular and Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
Valdés-Sánchez
Teresa
T
Llano
Elena
E
Menéndez
Luis
L
Baamonde
Ana
A
Denlinger
Bristol L
BL
Belmonte
Carlos
C
Juárez
Lucía
L
Lastra
Ana
A
García-Suárez
Olivia
O
Astudillo
Aurora
A
Kirstein
Martina
M
Pendás
Alberto M
AM
Fariñas
Isabel
I
López-Otín
Carlos
C
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009619:Nociceptors / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D014162:Transfection
D015820:Cadherins; D053504:Matrix Metalloproteinases, Membrane-Associated; C118502:Mmp24 protein, mouse