Folgueras Alicia R, Valdés-Sánchez Teresa, Llano Elena, Menéndez Luis, Baamonde Ana, Denlinger Bristol L, Belmonte Carlos, Juárez Lucía, Lastra Ana, García-Suárez Olivia, Astudillo Aurora, Kirstein Martina, Pendás Alberto M, Fariñas Isabel, López-Otín Carlos
Departamento de Bioquímica y Biología Molecular and Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
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.
伤害性感受纤维与肥大细胞之间的外周相互作用会导致炎性疼痛，但对于介导神经免疫通讯的机制却知之甚少。在此，我们表明金属蛋白酶MT5-MMP（MMP-24）是外周热痛觉和炎性痛觉过敏的重要介质。我们报道MT5-MMP由背根神经节中含降钙素基因相关肽（CGRP）的肽能伤害性感受器表达，且Mmp24基因缺陷小鼠在基础条件下对有害热刺激表现出增强的敏感性。同样，突变的肽能感觉神经元过度支配皮肤，该表型与细胞间粘附分子N-钙粘蛋白的调控性裂解变化相关。与基础痛觉不同，Mmp24(-/-)小鼠在炎症期间不会出现热痛觉过敏，该表型似乎与肥大细胞和感觉纤维之间N-钙粘蛋白介导的细胞间相互作用改变有关。总之，我们的研究结果证明了MT5-MMP在皮肤神经免疫突触形成中的重要作用，并表明这种金属蛋白酶可能是疼痛控制的一个靶点。
