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Recent studies have revealed non-neuronal functions of plasma Reelin in inflammation by promoting endothelial\u2013leukocyte adhesion through its canonical pathway in endothelial cells (via ApoER2 acting on NF-\u03baB), as well as in vascular tone regulation and thrombosis. In this study, we have investigated the safety and efficacy of selectively depleting plasma Reelin as a potential therapeutic strategy for chronic inflammatory diseases. We found that Reelin expression remains stable throughout adulthood and that peripheral anti-Reelin antibody treatment with CR-50 efficiently depletes plasma Reelin without affecting its levels or functionality within the CNS. Notably, this approach preserves essential neuronal functions and synaptic plasticity. Furthermore, in mice induced with experimental autoimmune encephalomyelitis (EAE), selective modulation of endothelial responses by anti-Reelin antibodies reduces pathological leukocyte infiltration without completely abolishing diapedesis. Finally, long-term Reelin depletion under metabolic stress induced by a Western diet did not negatively impact the heart, kidney, or liver, suggesting a favorable safety profile. These findings underscore the promising role of peripheral anti-Reelin therapeutic strategies for autoimmune diseases and conditions where endothelial function is compromised, offering a novel approach that may avoid the immunosuppressive side effects associated with conventional anti-inflammatory therapies.<\/jats:p>","DOI":"10.3390\/cells13070583","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T14:14:09Z","timestamp":1711548849000},"page":"583","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Safety of Anti-Reelin Therapeutic Approaches for Chronic Inflammatory Diseases"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6437-2119","authenticated-orcid":false,"given":"Laurent","family":"Calvier","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Alexander","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4880-1117","authenticated-orcid":false,"given":"Austin T.","family":"Marckx","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Z.","family":"Kounnas","sequence":"additional","affiliation":[{"name":"Reelin Therapeutics Inc., La Jolla, CA 92130, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4483-8166","authenticated-orcid":false,"given":"Murat","family":"Durakoglugil","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Herz","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Texas (UT) Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Center for Translational Neurodegeneration Research, UT Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,27]]},"reference":[{"key":"ref_1","first-page":"597395","article-title":"Reelin in the Years: Controlling Neuronal Migration and Maturation in the Mammalian Brain","volume":"2014","year":"2014","journal-title":"Adv. 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