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

Abstract

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 TREM2microglia 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, Trem2microglia 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 CD8T cells and CD19B cells, along with a reduction in forkhead box P3 (FOXP3)regulatory T cells in Trem2mice. CD8T 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.