# Complement, Inflammasome, and Microglial Crosstalk in Glaucoma: From Neurodegeneration to Immune-Based Precision Therapy

## TL;DR

Glaucoma is increasingly understood as a neurodegenerative disease driven by immune processes like complement activation and microglial activity, opening new avenues for precision therapies.

## Contribution

This paper reviews the role of complement, inflammasome, and microglial interactions in glaucoma and proposes a framework for immune-based precision therapy.

## Key findings

- Complement activation and NLRP3 inflammasome signaling contribute to retinal ganglion cell death in glaucoma.
- Microglia transition from protective to harmful states, amplifying neuroinflammation.
- Emerging therapies targeting immune pathways may offer precision treatment for glaucoma patients.

## Abstract

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-1β/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 ‘glaucoma’, ‘complement’, ‘inflammasome’, ‘NLRP3’, ‘microglia’, and ‘neuroinflammation’. 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.