title: Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation.
abstract: 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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular and Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Folgueras
authors.forename: Teresa
authors.initials: T
authors.lastname: Valdés-Sánchez
authors.forename: Elena
authors.initials: E
authors.lastname: Llano
authors.forename: Luis
authors.initials: L
authors.lastname: Menéndez
authors.forename: Ana
authors.initials: A
authors.lastname: Baamonde
authors.forename: Bristol L
authors.initials: BL
authors.lastname: Denlinger
authors.forename: Carlos
authors.initials: C
authors.lastname: Belmonte
authors.forename: Lucía
authors.initials: L
authors.lastname: Juárez
authors.forename: Ana
authors.initials: A
authors.lastname: Lastra
authors.forename: Olivia
authors.initials: O
authors.lastname: García-Suárez
authors.forename: Aurora
authors.initials: A
authors.lastname: Astudillo
authors.forename: Martina
authors.initials: M
authors.lastname: Kirstein
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Pendás
authors.forename: Isabel
authors.initials: I
authors.lastname: Fariñas
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: 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
chemical_list: D015820:Cadherins; D053504:Matrix Metalloproteinases, Membrane-Associated; C118502:Mmp24 protein, mouse