title: Decreased TNF Levels and Improved Retinal Ganglion Cell Survival in MMP-2 Null Mice Suggest a Role for MMP-2 as TNF Sheddase.
abstract: Matrix metalloproteinases (MMPs) have been designated as both friend and foe in the central nervous system (CNS): while being involved in many neurodegenerative and neuroinflammatory diseases, their actions appear to be indispensable to a healthy CNS. Pathological conditions in the CNS are therefore often related to imbalanced MMP activities and disturbances of the complex MMP-dependent protease network. Likewise, in the retina, various studies in animal models and human patients suggested MMPs to be involved in glaucoma. In this study, we sought to determine the spatiotemporal expression profile of MMP-2 in the excitotoxic retina and to unravel its role during glaucoma pathogenesis. We reveal that intravitreal NMDA injection induces MMP-2 expression to be upregulated in the Müller glia. Moreover, MMP-2 null mice display attenuated retinal ganglion cell death upon excitotoxic insult to the retina, which is accompanied by normal glial reactivity, yet reduced TNF levels. Hence, we propose a novel in vivo function for MMP-2, as an activating sheddase of tumor necrosis factor (TNF). Given the pivotal role of TNF as a proinflammatory cytokine and neurodegeneration-exacerbating mediator, these findings generate important novel insights into the pathological processes contributing to glaucomatous neurodegeneration and into the interplay of neuroinflammation and neurodegeneration in the CNS.
authors.affiliation: Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Naamsestraat 61, 3000 Leuven, Belgium.
authors.forename: Lies
authors.initials: L
authors.lastname: De Groef
authors.affiliation: Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Naamsestraat 61, 3000 Leuven, Belgium.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salinas-Navarro
authors.affiliation: Inflammation Research Center, VIB, FSVM Building, Technologiepark 927, 9052 Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, FSVM Building, Technologiepark 927, 9052 Ghent, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Van Imschoot
authors.affiliation: Inflammation Research Center, VIB, FSVM Building, Technologiepark 927, 9052 Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, FSVM Building, Technologiepark 927, 9052 Ghent, Belgium.
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.affiliation: Inflammation Research Center, VIB, FSVM Building, Technologiepark 927, 9052 Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, FSVM Building, Technologiepark 927, 9052 Ghent, Belgium.
authors.forename: Roosmarijn E
authors.initials: RE
authors.lastname: Vandenbroucke
authors.affiliation: Laboratory of Neural Circuit Development and Regeneration, Animal Physiology and Neurobiology Section, Department of Biology, KU Leuven, Naamsestraat 61, 3000 Leuven, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
mesh_terms: D000818:Animals; D015153:Blotting, Western; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016202:N-Methylaspartate; D020778:Matrix Metalloproteinase 2