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HMGB1 and Caveolin-1 related to RPE cell senescence in age-related macular degeneration
Shuo Sun1, Bincui Cai1, Yao Li2,3
1Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, People's Republic of China.
Abstract:
Accumulation of lipofuscin in the retinal pigment epithelium (RPE) is considered a major cause of RPE dysfunction and senescence in age-related macular degeneration (AMD), and N-retinylidene-N-retinylethanolamine (A2E) is the main fluorophore identified in lipofuscin from aged human eyes. Here, human-induced pluripotent stem cell (iPSC)-RPE was generated from healthy individuals to reveal proteomic changes associated with A2E-related RPE cell senescence. A novel RPE cell senescence-related protein, high-mobility group box 1 (HMGB1), was identified based on proteomic mass spectrometry measurements on iPSC-RPE with A2E treatment. Furthermore, HMGB1 upregulated Caveolin-1, which also was related RPE cell senescence. To investigate whether changes in HMGB1 and Caveolin-1 expression under A2E exposure contribute to RPE cell senescence, human ARPE-19 cells were stimulated with A2E; expression of HMGB1, Caveolin-1, tight junction proteins and senescent phenotypes were verified. HMGB1 inhibition alleviated A2E induced cell senescence. Migration of RPE cells was evaluated. Notably, A2E less than or equal to 10μM induced both HMGB1 and Caveolin-1 protein upregulation and HMGB1 translocation, while Caveolin-1 expression was downregulated when there was more than 10μM A2E. Our data indicate that A2E-induced upregulation of HMGB1、Caveolin-1 and HMGB1 release may relate to RPE cell senescence and play a role in the pathogenesis of AMD.
Insights
Lipofuscin accumulation, driven by N-retinylidene-N-retinylethanolamine (A2E), causes retinal pigment epithelium (RPE) cell senescence in age-related macular degeneration (AMD). High-mobility group box 1 (HMGB1) and Caveolin-1 are identified as key proteins involved in this process.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Medicine
Background:
- Lipofuscin accumulation in the retinal pigment epithelium (RPE) is a hallmark of aging and a key factor in age-related macular degeneration (AMD).
- N-retinylidene-N-retinylethanolamine (A2E) is the primary fluorescent component of lipofuscin, contributing to RPE cell dysfunction and senescence.
Purpose of the Study:
- To investigate the proteomic changes in RPE cells associated with A2E-induced senescence.
- To identify novel proteins involved in RPE cell senescence and their role in AMD pathogenesis.
Main Methods:
- Generation of human-induced pluripotent stem cell (iPSC)-RPE from healthy individuals.
- Proteomic mass spectrometry to analyze protein expression in A2E-treated iPSC-RPE.
- Stimulation of human ARPE-19 cells with A2E to verify HMGB1 and Caveolin-1 roles, including expression, translocation, and impact on senescent phenotypes and cell migration.
Main Results:
- High-mobility group box 1 (HMGB1) was identified as a novel RPE cell senescence-related protein upregulated by A2E.
- HMGB1 was found to upregulate Caveolin-1, another protein implicated in RPE cell senescence.
- HMGB1 inhibition alleviated A2E-induced RPE cell senescence, and HMGB1 translocation was observed with A2E treatment. Caveolin-1 expression showed a dose-dependent response to A2E concentration.
Conclusions:
- A2E-induced upregulation of HMGB1 and Caveolin-1, along with HMGB1 release, are implicated in RPE cell senescence.
- These molecular changes may contribute to the pathogenesis of age-related macular degeneration (AMD).
- HMGB1 and Caveolin-1 represent potential therapeutic targets for AMD.
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