TREM2-Mediated Myeloid Cells Protect Against Pathological Choroidal Neovascularization

Choroidal neovascularization (CNV) is a hallmark of neovascular age-related macular degeneration, a leading cause of irreversible vision loss in the elderly. While immune dysregulation and myeloid cell activation have been implicated in CNV pathogenesis, the molecular mechanisms by which myeloid subsets influence NV remain incompletely understood. Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunomodulatory receptor enriched in microglia and tissue macrophages, known to play protective roles in retinal and neurodegenerative diseases. However, its function in CNV has not been fully characterized. In this study, we investigated the role of TREM2 in CNV using transcriptomic, genetic, and functional approaches. Single-cell RNA sequencing revealed selective upregulation of Trem2 in activated microglia and macrophages following laser-induced CNV. These findings were validated at the protein level using immunostaining, which confirmed robust TREM2 expression in lesion-associated IBA1⁺ myeloid cells. Functionally, Trem2 haploinsufficiency exacerbated CNV lesion size and vascular leakage, indicating a protective role in disease modulation. Transcriptomic profiling demonstrated that Trem2-expressing myeloid cells exhibit distinct angiogenic and inflammasome-related gene signatures, suggesting that TREM2 regulates angiogenesis through modulation of inflammatory pathways. We further examined the functional interaction between TREM2 and suppressor of cytokine signaling 3 (SOCS3), another anti-inflammatory mediator upregulated during CNV. Using compound mutant mice, we showed that Trem2 and SOCS3 function through overlapping but independent anti-angiogenic programs, and their combined deficiency leads to additive worsening of CNV pathology. These findings establish TREM2 as a key regulator of myeloid cell function and angiogenesis in the diseased retina.