The Dual Role of Macroglia in Glaucoma: Deciphering the Contributions of Astrocytes and Müller Cells to Retinal Neurodegeneration and Neuroprotection

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’s pathophysiology. In the healthy retina, astrocytes and Müller 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 Müller 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.