Les Métalloprotéases de la matrice et leurs inhibiteurs, des modulateurs des interactions neuro-immunes et des processus physiopathologiques dans le système nerveux

Matrix Metalloproteinases and their Inhibitors, Modulators of Neuro-Immune Interactions and of Pathophysiological Processes in the Nervous System

Neurobiologie des Interactions Cellulaires et Neurophysiopathologie (N.I.C.N.) FRE CNRS 2533, Université de la Méditerranée, Faculté de Médecine, IFR Jean Roche, 27 Bd Jean Moulin. 13385 Marseille Cedex 05. Tel : 04 91 32 44 19. Fax : 04 91 25 89 70. e-mail : khrestchatisky.m@jean-roche.univ-mrs.fr

Résumé

Les métalloprotéases matricielles (MMPs) régulent ou dégradent par clivage protéolytique des composants de la matrice extracellulaire, des cytokines et chimiokines, des protéines d’adhérence et de multiples récepteurs membranaires. Le contrôle de l’activité des MMPs par leurs inhibiteurs physiologiques, les TIMPs, participe à l’homéostasie tissulaire. Par contre, la perte de ce contrôle est associée à des processus pathologiques impliquant inflammation, prolifération ou mort cellulaire et remaniements tissulaires. Le système MMP/TIMP est impliqué dans le développement et la fonction des cellules du système immunitaire, en permettant leur différenciation, leur activation, leur migration à travers les membranes basales et dans les tissus. Nous résumons ici les résultats récents qui montrent que le système MMP/TIMP participerait non seulement aux interactions neuro-immunes mais jouerait également un rôle central dans la physiopathologie du système nerveux où les MMPs pourraient constituer de nouvelles cibles thérapeutiques.

Abstract

The matrix metalloproteinases (MMPs) belong to a growing family of Zn²⁺-dependent endopeptidases, secreted or membrane-bound (MT-MMP), that regulate or degrade by proteolytic cleavage protein components of the extracellular matrix, cytokines, chemokines, cell adhesion molecules and a variety of membrane receptors. MMP activity is counterbalanced by their physiological inhibitors, the tissue inhibitors of MMPs (TIMPs), a family of 4 secreted multifunctional proteins that have growth promoting activities. In physiological conditions MMP activity is tightly regulated and altered MMP regulation is associated with pathological processes including inflammation, cell proliferation, cell death and tissue remodeling. The MMP/TIMP system is involved in the development and function of cells of the immune system by promoting their differentiation, activation, migration across basement membranes and tissues. In the last years, data has accumulated indicating that the MMP/TIMP system is expressed in the nervous system where it regulates neuro-immune interactions and plays a major role in pathophysiological processes. In this review, we present recent in vivo and in vitro studies that highlight the contribution of the MMP/TIMP system to various diseases of the nervous system, involving blood brain barrier breakdown, neuroinflammation, glial reactivity, neuronal death, reactive plasticity, and to developmental and physiological processes including cell migration, axonal sprouting and neuronal plasticity. This review also alludes to the beneficial effects of synthetic MMP inhibitors in different animal models of neuropathology. In all, a further understanding of the role of MMPs and TIMPs in the nervous system should contribute to unravel mechanisms of neuronal plasticity and pathology and set the basis of new therapeutic strategies in nervous system disorders based on the development of synthetic MMP inhibitors.