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In this study, we investigated how systemic lipopolysaccharide (LPS)-induced inflammation influences retinal microglial activation and RGC vulnerability under physiological conditions and after traumatic ON damage. In adult female rats, systemic LPS administration by intraperitoneal injection induced rapid and robust microglial activation, characterized by process retraction and soma hypertrophy within hours and promoting microglial proliferation at later stages but without causing RGC loss in intact retinas. Following ON crush, systemic inflammation did not affect early RGC degeneration but significantly exacerbated neuronal loss during the late acute phase. This increased vulnerability was accompanied by a marked rise in microglial density and a pronounced redistribution of microglia toward the central retina and the ON head, a region of heightened anatomical and metabolic susceptibility. Together, these findings demonstrate that, in rats, systemic inflammation alone is insufficient to induce RGC degeneration but acts as a potent priming factor that amplifies neurodegeneration in the context of axonal injury. The temporal and spatial specificity of microglial responses underscores their context-dependent role in retinal pathology and identifies systemic inflammatory status as a critical determinant of retinal outcome after trauma. Targeted, time-dependent modulation of microglial activation may therefore represent a promising therapeutic strategy for optic neuropathies.<\/jats:p>","DOI":"10.3390\/ijms27031502","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T12:46:11Z","timestamp":1770122771000},"page":"1502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Systemic Inflammation Aggravates Retinal Ganglion Cell Vulnerability to Optic Nerve Trauma in Adult Rats"],"prefix":"10.3390","volume":"27","author":[{"given":"Giuseppe","family":"Rovere","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain"},{"name":"Department of Clinical Science and Translational Medicine, Section of Orthopaedics and Traumatology, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Policlinico Tor Vergata University Hospital, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Caja-Matas","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain"},{"name":"Hospital General Universitario Santa Luc\u00eda, 30202 Cartagena, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9352-1400","authenticated-orcid":false,"given":"Beatriz","family":"Vidal-Villegas","sequence":"additional","affiliation":[{"name":"Department of Immunology, Ophthalmology and ENT, Faculty of Medicine, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Bernal-Garro","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"Sobrado-Calvo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Salinas-Navarro","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Nucci","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5734-482X","authenticated-orcid":false,"given":"Mar\u00eda Paz","family":"Villegas-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9216-1615","authenticated-orcid":false,"given":"Manuel","family":"Vidal-Sanz","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8566-9277","authenticated-orcid":false,"given":"Marta","family":"Agudo-Barriuso","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4121-514X","authenticated-orcid":false,"given":"Francisco M.","family":"Nadal-Nicol\u00e1s","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, University of Murcia and Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), 30120 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41392-023-01486-5","article-title":"Role of Neuroinflammation in Neurodegeneration Development","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. 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