{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:26:27Z","timestamp":1790724387816,"version":"4.1.0"},"reference-count":100,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T00:00:00Z","timestamp":1771891200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Glaucoma is no longer viewed solely as a pressure-mediated optic neuropathy but as a chronic neurodegenerative disease with a strong immune component. Across experimental models and patient samples, convergent inflammatory circuitry complement activation, NLRP3 inflammasome signaling, and microglial reactivity emerge as a central driver of retinal ganglion cell (RGC) dysfunction and death. Local complement upregulation (C1q, C3, C5) in the retina and optic nerve head (ONH) promotes aberrant synaptic tagging, phagoptosis, and membrane attack complex stress. In parallel, biomechanical strain, ischemia, mitochondrial damage, and danger-associated molecular patterns prime and activate the NLRP3 inflammasome in microglia, astrocytes, and ONH cells, leading to caspase-1 activation, IL-1\u03b2\/IL-18 maturation, and pyroptotic or apoptotic injury. Microglia integrate these cues, shifting from early protective surveillance to chronic maladaptive states that amplify complement and inflammasome outputs. This review synthesizes mechanistic links within the complement NLRP3 microglia axis, considers systemic and adaptive immune contributions, and proposes a translational framework for immune-based clinical stratification. The literature for this review was identified through searches of PubMed, Web of Science, and Scopus using combinations of the terms \u2018glaucoma\u2019, \u2018complement\u2019, \u2018inflammasome\u2019, \u2018NLRP3\u2019, \u2018microglia\u2019, and \u2018neuroinflammation\u2019. Priority was given to recent experimental, translational, and clinical studies. We then evaluate emerging immunomodulatory therapies, complement inhibitors, inflammasome blockers, microglial state reprogrammers, cytokine biologics, and cell-derived immunoregulatory approaches, highlighting biomarkers and trial design needs. An immune systems view of glaucoma enables precision neuroprotection for patients who progress despite controlled intraocular pressure.<\/jats:p>","DOI":"10.3390\/life16030368","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T12:19:23Z","timestamp":1771935563000},"page":"368","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Complement, Inflammasome, and Microglial Crosstalk in Glaucoma: From Neurodegeneration to Immune-Based Precision Therapy"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8815-8684","authenticated-orcid":false,"given":"Tony Yihao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China"},{"name":"NHC Key Laboratory of Myopia, Fudan University, Shanghai 200032, China"},{"name":"Key Laboratory of Myopia, Chinese Academy of Medical Sciences, National Health Commission, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China"},{"name":"NHC Key Laboratory of Myopia, Fudan University, Shanghai 200032, China"},{"name":"Key Laboratory of Myopia, Chinese Academy of Medical Sciences, National Health Commission, Shanghai 200031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghuai","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200032, China"},{"name":"NHC Key Laboratory of Myopia, Fudan University, Shanghai 200032, China"},{"name":"Key Laboratory of Myopia, Chinese Academy of Medical Sciences, National Health Commission, Shanghai 200031, China"},{"name":"Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai 200031, China"},{"name":"State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101223","DOI":"10.1016\/j.mam.2023.101223","article-title":"Advances in understanding glaucoma pathogenesis: A multifaceted molecular approach for clinician scientists","volume":"94","author":"Ekici","year":"2023","journal-title":"Mol. 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