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Published on: October 27, 2017
Retinal Pigment Epithelium Extracellular Vesicles Induce Microglia Polarization in MERTK-Associated Retinal
Hang Zhang1,2, Zhen-Yu Liu1, Lingzi Wu1
1Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Purpose:
Retinitis pigmentosa (RP) is a hereditary retinal disease. MERTK-associated RP is characterized by earlier onset and rapid progression, featuring retinal pigment epithelium (RPE) inflammation and microglial activation, yet the underlying mechanisms remain incompletely understood. The study aimed to elucidate the intrinsic interactions between RPE inflammation and microglial activation mediated by RPE-derived extracellular vesicles (EVs).
Methods:
Induced pluripotent stem cell (iPSC)-derived RPE models from MERTK mutant patients and healthy controls were established and characterized by transcriptomic analysis. RPE-derived EVs were isolated, and their RNA and protein cargo were systematically profiled using transcriptomic and proteomic data, revealing a potential role in retinal inflammation regulation. The effects of RPE-EVs on microglial activation were confirmed through in vitro co-culture and in vivo animal experiments.
Results:
Transcriptomic analysis revealed that differentially expressed genes between MERTK mut-RPE (M-RPE) and control RPE (C-RPE) were enriched in inflammatory signaling pathways and EV-related terms. Multi-omics data further indicated that the altered RNA and protein cargo of M-RPE-derived EVs were closely associated with inflammation and immune regulation. In vitro co-culture confirmed that M-EVs could rapidly activate microglia and upregulate pro-inflammatory factors. In vivo experiments indicated that microglia phagocytosed M-EVs exhibited more pronounced M1 polarization and migratory changes.
Conclusions:
RPE-derived EVs act as critical drivers of microglial M1 polarization in MERTK-associated RP. Our study revealed their pivotal role in the progression of early-onset severe RP, providing theoretical support for the potential of targeting EVs to modulate the retinal immune microenvironment and intervene in the progression of retinal degeneration.
Insights
Extracellular vesicles (EVs) derived from retinal pigment epithelium (RPE) drive microglial activation in MERTK-associated retinitis pigmentosa (RP). Targeting these EVs may offer a new therapeutic strategy for retinal degeneration.
Area of Science:
- Ophthalmology
- Genetics
- Immunology
Background:
- Retinitis pigmentosa (RP) is a hereditary retinal disease.
- MERTK-associated RP presents with early onset and rapid progression, involving retinal pigment epithelium (RPE) inflammation and microglial activation.
- The precise mechanisms linking RPE inflammation and microglial activation in MERTK-RP remain unclear.
Purpose of the Study:
- To investigate the role of RPE-derived extracellular vesicles (EVs) in mediating interactions between RPE inflammation and microglial activation in MERTK-associated RP.
- To elucidate the molecular cargo of RPE-derived EVs and their impact on microglial responses.
Main Methods:
- Established induced pluripotent stem cell (iPSC)-derived RPE models from MERTK mutant and healthy control patients.
- Isolated and characterized RPE-derived EVs, profiling their RNA and protein content.
- Utilized in vitro co-culture and in vivo animal models to assess the effects of RPE-EVs on microglial activation.
Main Results:
- Transcriptomic analysis revealed enrichment of inflammatory and EV-related pathways in MERTK mutant RPE.
- Multi-omics data showed altered RNA and protein cargo in EVs from MERTK mutant RPE, associated with inflammation.
- In vitro and in vivo studies confirmed that MERTK-RPE-derived EVs promote microglial activation, M1 polarization, and migration.
Conclusions:
- RPE-derived EVs are key drivers of microglial M1 polarization in MERTK-associated RP.
- These EVs play a critical role in the progression of early-onset severe RP.
- Targeting EVs presents a potential strategy to modulate the retinal immune microenvironment and combat retinal degeneration.
