Temporal biphasic regulation of photoreceptor degeneration by microglial TREM2: A metabolic-immune nexus in retinitis pigmentosa

Retinitis pigmentosa (RP), the leading cause of inherited blindness, lacks therapies because of undefined photoreceptor degeneration mechanisms. While microglia/myeloid cells drive RP progression, their phenotype-regulating determinants remain unclear. Using rd10 mice, we reveal TREM2 as a biphasic RP regulator via STAT2-mediated microglial reprogramming. Early TREM2 loss amplifies neuroinflammation through STAT2 hyperactivation, while late deficiency triggers NF-κB/STAT2-driven microglial apoptosis, impairing phagocytosis yet preserving photoreceptors. We uncover a photoreceptor-microglia metabolic axis where apoptotic photoreceptors release arachidonic acid, salicylic acid, and creatinine to induce STAT2-dependent apoptosis in TREM2-deficient cells. Crucially, we identify intermicroglia PSAP/GPR37 signaling as a self-propagating apoptotic mechanism-the first evidence of apoptotic transmission in retinal degeneration. This study establishes three advances: (i) TREM2 exhibits stage-dependent neuroprotective/neurotoxic roles, (ii) photoreceptor metabolites dictate microglia/myeloid cell fate via STAT2, and (iii) microglial apoptosis spreads through membrane signaling complexes. Our findings redefine neuroimmune dynamics in retinal degeneration, propose chronotherapeutic TREM2 targeting, and extend to Alzheimer's and other microglia-associated CNS disorders via metabolic-immune interplay.