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Elevated intraocular pressure (IOP) is a major risk factor for glaucoma; however, it is neither necessary nor sufficient for glaucomatous neurodegeneration, as patients can exhibit high IOP without developing glaucoma and patients can develop glaucoma with normal IOP. Yet FDA-approved treatment options are largely limited to approaches to minimize risk and reduce IOP. Thus, there is a critical need to target other aspects of glaucoma pathophysiology. Neuroinflammation is broadly defined here as immune-relevant responses, often involving microglia and astrocytes, within the central nervous system which may include peripheral immune cell infiltration. Burgeoning evidence has implicated glia in the development and progression of glaucoma in human tissues and mouse models. Most mouse models of glaucoma to date have shown that microglia and astrocytes are reactive in early stages of glaucomatous neurodegeneration prior to overt RGC loss. However, there is growing evidence that human and mouse glia adopt distinct phenotypes in response to neurodegeneration. Thus, there is critical need to expand our studies to include the new generations of human cell culture models. In this review, we discuss: 1) the evidence of neuroinflammatory processes in human glaucoma; 2) models of glaucoma relevant neuroinflammation; and the evidence specifically for 3) innate immune cell-driven and 4) macroglia-driven processes.<\/jats:p>","DOI":"10.1007\/s00335-026-10253-0","type":"journal-article","created":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T18:53:04Z","timestamp":1782586384000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neuroinflammation in glaucoma: a myriad of cellular pathways and players"],"prefix":"10.1007","volume":"37","author":[{"given":"Michael","family":"MacLean","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean D.","family":"Lydon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e1tia","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Pizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory A.","family":"Diemler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E. 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