ArticleScience advances2025
Temporal biphasic regulation of photoreceptor degeneration by microglial TREM2: A metabolic-immune nexus in retinitis pigmentosa.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- EGFR inhibition promotes functional engraftment and graft survival via donor-derived CHI3L1 in fetal RPE suspension transplantation.Cell reports. Medicine · 2026Article
- TREM2 restrains myeloid inflammasome activation to protect against photoreceptor degeneration.Journal of neuroinflammation · 2026Article
- TPM1 drives cytoskeleton-immunometabolism coupling and LGALS9/CD45-mediated neuroinflammatory propagation in retinitis pigmentosa.Science advances · 2026Article
- Targeting MEF2A suppresses microglial hyperactivation and synaptic phagocytosis to attenuate epilepsy pathogenesis.Cell death & disease · 2026Article
- Targeting the CCL7-STAT1 axis attenuates microglial neurotoxicity and photoreceptor degeneration in retinitis pigmentosa.Journal of neuroinflammation · 2026Article
- TREM2 in age-related macular degeneration: a microglia-centered perspective in the retinal myeloid landscape.Frontiers in ophthalmology · 2026Review
- Photoreceptor outer segments promote the accumulation of lipid droplets in microglia by reprogramming lipid metabolism.Frontiers in immunology · 2026Article
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Authors and funding
5 authors.
Funding
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Abstract
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.
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