TREM2 restrains myeloid inflammasome activation to protect against photoreceptor degeneration.

Myeloid cells, including infiltrating macrophages and resident microglia, are critical regulators of retinal homeostasis and respond rapidly to photoreceptor stress. Dysregulated myeloid responses, however, can exacerbate retinal degeneration. Triggering receptor expressed on myeloid cells 2 (TREM2) modulates phagocytosis, metabolism, and inflammatory signaling, yet its role in retinal degeneration remains incompletely understood. Here, we investigated TREM2 function in the retinal degeneration 10 (rd10) mouse model of inherited retinal degeneration, characterized by progressive photoreceptor loss and robust myeloid cell activation. TREM2 expression was upregulated in degenerating retinas, and global TREM2-deficiency in rd10 mice exhibited accelerated photoreceptor cell death, reduced outer nuclear layer thickness, disrupted retinal pigment epithelium integrity, and altered microglial spatial dynamics. Single-cell transcriptomics revealed that TREM2-positive microglia express APOE-associated and interferon-primed programs. Global TREM2 deficiency was associated with increased inflammasome-related signaling in retinal myeloid cells, including elevated cleaved caspase-1, cleaved gasdermin D, and mature interleukin-1β, linking amplified immune priming to pyroptotic signaling. Genetic or pharmacological inhibition of gasdermin D significantly mitigated photoreceptor loss in global TREM2-deficient rd10 retinas, demonstrating a functional contribution of inflammasome-associated responses to disease exacerbation. Together, these findings support a protective role for TREM2-associated immune regulation in the degenerating retina and identify downstream inflammasome pathways as potential therapeutic targets in retinal degenerative diseases.