Loss of Triggering Receptor Expressed on Myeloid Cells 2 Impairs Microglial Function and Exacerbates Retinal Neurodegeneration in Glaucoma.

Glaucoma is a leading cause of irreversible blindness, characterized by retinal ganglion cell degeneration and neuroinflammation. Retinal microglia are key modulators of this pathology. Using single-cell transcriptomic analysis of human glaucomatous retinas, a distinct population of disease-associated microglia (DAM) was identified, defined by elevated triggering receptor expressed on myeloid cells 2 (TREM2) and other neurodegeneration-related genes. DAM exhibited enriched transcriptional programs associated with phagocytosis, antigen presentation, and immune regulation, with TREM2high microglia predominating. In a mouse model of retinal ischemia-reperfusion injury, Trem2 knockout (Trem2-/-) mice exhibited exacerbated retinal neurodegeneration and neuroinflammation, impaired microglial phagocytosis, and antigen presentation relative to wild-type controls. Furthermore, Trem2-/- microglia failed to acquire a DAM-like or anti-inflammatory (M2) phenotype, instead adopting a proinflammatory (M1)-skewed state. Flow cytometry and immunofluorescence analyses of cervical lymph nodes revealed increased frequencies of CD8+ T cells and CD19+ B cells, along with a reduction in forkhead box P3 (FOXP3)+ regulatory T cells in Trem2-/- mice. CD8+ T cells displayed heightened proliferation and diminished exhaustion, indicating sustained effector function. Transcriptomic profiling further confirmed enhanced lymphocyte activation, inflammasome signaling, and suppression of immunoregulatory pathways, including transforming growth factor-β and IL-2 signaling critical for regulatory T cell induction. Collectively, these findings establish TREM2 as a central regulator of disease-associated microglial activation and immune homeostasis in glaucoma. Loss of TREM2 compromises both innate and adaptive immune regulation, leading to sustained inflammation and exacerbated retinal neurodegeneration.