Dual immune armies in glaucoma: microglia and monocyte-derived macrophages

Glaucoma is a leading cause of irreversible blindness globally, with the core pathological feature being progressive degeneration of retinal ganglion cells. Neuroinflammation pervades the entire course of glaucoma, and an imbalance in the intraocular immune microenvironment is critical factor underlying progression. As an extension of the central nervous system, the retina has a unique immune microenvironment. Under physiological conditions, microglia, which are primary tissue-resident immune cells, maintain homeostasis. In pathological states, the blood-retinal barrier is compromised and allows monocyte-derived macrophages (MDMs) to infiltrate the retinal tissue. We introduce the concept of “dual immune armies, ” specifically referring to the core retinal immune population comprising microglia and MDMs. These two cell types coordinate to form an immune network, but they demonstrate significant functional heterogeneity during glaucoma pathogenesis. Microglia act as first responders and activate rapidly during the early stages of injury, monitor changes in the microenvironment in real time, and initiate the primary inflammatory response. MDMs serve as “late-reinforcement troops” and infiltrate extensively following blood-retinal barrier disruption, amplify the inflammatory cascade, and exacerbate optic nerve damage. Previous studies have often conflated these two cell types, leading to a lack of precise targets for immune intervention in glaucoma. Based on recent research, this study systematically compared the origins, functions, and specific marker profiles of microglia and MDMs with a focus on elucidating their synergistic roles and functional division of labor in glaucomatous optic neuropathy. Elucidating the heterogeneity of these two immune cell populations and their precisely regulated functions at different disease stages will help clarify the key mechanisms underlying the imbalance of the retinal immune microenvironment in glaucoma. It will also provide a new theoretical basis and research direction for the development of targeted immunomodulatory strategies to protect retinal ganglion cells and potentially reverse optic nerve damage.