From homeostasis to neurodegeneration: Müller glia in retinal disease

Müller glia are the principal macroglia cells of the retina and are essential for maintaining structural, metabolic, synaptic, and vascular homeostasis. They regulate neurotransmitter recycling, ion and water balance, antioxidant defense, and neurovascular coupling, positioning them as central coordinators of retinal function in health and disease. In response to injury or stress, Müller glia transition from homeostatic support to reactive states that may initially preserve tissue integrity but, when sustained, contribute to chronic neuroinflammation, barrier dysfunction, and neuronal degeneration. In this review, we examine the core physiological functions of Müller glia and highlight emerging evidence that their responses are heterogeneous, reflecting spatial, molecular, and disease-specific differences across retinal layers and pathological contexts. We discuss major drivers of Müller glia activation, including mechanical stress, metabolic and oxidative imbalance, and inflammatory signaling, with emphasis on convergent pathways such as gp130–JAK–STAT3, NFκB, and mechanosensitive calcium signaling. We then consider how disruption of Müller glia homeostatic functions contributes to retinal disease, focusing on glaucoma, diabetic retinopathy, and age-related macular degeneration. Across these disorders, Müller glia emerge not as passive support cells, but as active regulators of neuronal and vascular microenvironments whose state of transition may shape disease progression. Finally, we discuss therapeutic strategies aimed at modulating Müller glia states, including lipid metabolism and signaling, restoration of ion and metabolic homeostasis, gene-based targeting, and regenerative reprogramming, and consider how single-cell, spatial, and multi-omic approaches define distinct layers of Müller glia state. Defining when and how Müller glia shift from adaptive to maladaptive states will be critical for developing therapies that restore retinal homeostasis and limit neurodegeneration.