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While being part of the NVU, astrocytes have been largely overlooked in this context and only recently, tightening of the glia limitans has been put forward as an important neuroprotective response to limit these injurious processes. In this study, using the retina as a central nervous system (CNS) model organ, we investigated the structure and function of the glia limitans, and reveal that the blood\u2013retina barrier and glia limitans function as a coordinated double barrier to limit infiltration of leukocytes and immune molecules. We provide in vitro and in vivo evidence for a protective response at the NVU upon CNS injury, which evokes inflammation\u2010induced glia limitans tightening. Matrix metalloproteinase\u20103 (MMP\u20103) was found to be a crucial regulator of this process, thereby revealing its beneficial and immunomodulatory role in the CNS. in vivo experiments in which MMP\u20103 activity was deleted via genetic and pharmacological approaches, combined with a comprehensive study of tight junction molecules, glial end feet markers, myeloid cell infiltration, cytokine expression and neurodegeneration, show that MMP\u20103 attenuates neuroinflammation and neurodegeneration by tightening the glia limitans, thereby pointing to a prominent role of MMP\u20103 in preserving the integrity of the NVU upon injury. Finally, we gathered promising evidence to suggest that IL1b, which is also regulated by MMP\u20103, is at least one of the molecular messengers that induces glia limitans tightening in the injured CNS.<\/jats:p>","DOI":"10.1002\/glia.23875","type":"journal-article","created":{"date-parts":[[2020,7,9]],"date-time":"2020-07-09T16:06:26Z","timestamp":1594310786000},"page":"2643-2660","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Tightening the retinal glia limitans attenuates neuroinflammation after optic nerve injury"],"prefix":"10.1002","volume":"68","author":[{"given":"Evy","family":"Lefevere","sequence":"first","affiliation":[{"name":"Neural Circuit Development and Regeneration Research Group, Department of Biology KU Leuven  Leuven Belgium"},{"name":"Leuven Brain Institute (LBI) KU Leuven  Leuven 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Visual Neuroscience UCL Institute of Ophthalmology  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tine","family":"Van Bergen","sequence":"additional","affiliation":[{"name":"Oxurion NV  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge","family":"Van Hove","sequence":"additional","affiliation":[{"name":"Neural Circuit Development and Regeneration Research Group, Department of Biology KU Leuven  Leuven Belgium"},{"name":"Oxurion NV  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiavash","family":"Movahedi","sequence":"additional","affiliation":[{"name":"Myeloid Cell Immunology Lab VIB Center for Inflammation Research  Brussels Belgium"},{"name":"Lab of Cellular and Molecular Immunology Vrije Universiteit Brussel  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roosmarijn E.","family":"Vandenbroucke","sequence":"additional","affiliation":[{"name":"Barriers 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