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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Glaucoma is a leading cause of irreversible vision loss characterized by the progressive degeneration of retinal ganglion cells (RGCs) and structural and biochemical remodeling of the optic nerve head. Although lowering intraocular pressure remains the primary clinical intervention, neurodegeneration often persists, highlighting the complexity and multiple mechanisms involved in the disease\u2019s pathophysiology. In the healthy retina, astrocytes and M\u00fcller cells maintain structural integrity, homeostatic balance, and metabolic support. However, sustained pathological stress triggers reactive gliosis, a phenomenon with a dichotomous phenotype. Initially, the macroglial response is adaptive and neuroprotective. Persistent biomechanical and ischemic insults shift this profile into a typically deleterious one, characterized by extracellular matrix remodeling, complement system activation, and heightened neuroinflammation, factors that intensify RGC death. Mechanosensitive pathways, notably Piezo1 and various transient receptor potential (TRP) channels, emerge as critical sensors translating physical stress into these reactive cascades within interconnected multicellular networks. This review examines the crucial role of astrocytes and M\u00fcller cells in the dynamic modulation of the retinal microenvironment during glaucomatous progression. Finally, it discusses the therapeutic potential of macroglia-directed pharmacological or gene therapies to reprogram the retinal environment.<\/jats:p>","DOI":"10.3390\/ijms27156895","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6895","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Dual Role of Macroglia in Glaucoma: Deciphering the Contributions of Astrocytes and M\u00fcller Cells to Retinal Neurodegeneration and Neuroprotection"],"prefix":"10.3390","volume":"27","author":[{"given":"Guilherme Ribeiro","family":"Teixeira","sequence":"first","affiliation":[{"name":"Laboratory of Retinal Neurobiology, Department of Neurobiology, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"},{"name":"Graduate Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Gabriela Alves","family":"Costa","sequence":"additional","affiliation":[{"name":"Laboratory of Retinal Neurobiology, Department of Neurobiology, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"},{"name":"Graduate Program of Biomedical Sciences, Biomedical Institute, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0798-8372","authenticated-orcid":false,"given":"Ana Carolina de Luca","family":"Mattos","sequence":"additional","affiliation":[{"name":"Laboratory of Retinal Neurobiology, Department of Neurobiology, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"},{"name":"Graduate Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1115-725X","authenticated-orcid":false,"given":"Daniel","family":"Souza Monteiro de Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Graduate Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7070-3348","authenticated-orcid":false,"given":"Rafael","family":"Brito","sequence":"additional","affiliation":[{"name":"Graduate Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"},{"name":"Laboratory of Neuronal Physiology and Pathology, Department of Molecular and Cellular Biology, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1199-1826","authenticated-orcid":false,"given":"Karin da Costa","family":"Calaza","sequence":"additional","affiliation":[{"name":"Laboratory of Retinal Neurobiology, Department of Neurobiology, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"},{"name":"Graduate Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"},{"name":"Graduate Program of Biomedical Sciences, Biomedical Institute, Fluminense Federal University, Niter\u00f3i 242102401, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/bjo.2005.081224","article-title":"The Number of People with Glaucoma Worldwide in 2010 and 2020","volume":"90","author":"Quigley","year":"2006","journal-title":"Br. 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