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PDGF-D-induced immunoproteasome activation and cell-cell interactions
Jianing Zhang1, Wanhong Li1, Zhen Xiong1
1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, Guangdong, China.
Abstract:
Platelet-derived growth factor-D (PDGF-D) is abundantly expressed in ocular diseases. Yet, it remains unknown whether and how PDGF-D affects ocular cells or cell-cell interactions in the eye. In this study, using single-cell RNA sequencing (scRNA-seq) and a mouse model of PDGF-D overexpression in retinal pigment epithelial (RPE) cells, we found that PDGF-D overexpression markedly upregulated the key immunoproteasome genes, leading to increased antigen processing/presentation capacity of RPE cells. Also, more than 6.5-fold ligand-receptor pairs were found in the PDGF-D overexpressing RPE-choroid tissues, suggesting markedly increased cell-cell interactions. Moreover, in the PDGF-D-overexpressing tissues, a unique cell population with a transcriptomic profile of both stromal cells and antigen-presenting RPE cells was detected, suggesting PDGF-D-induced epithelial-mesenchymal transition of RPE cells. Importantly, administration of ONX-0914, an immunoproteasome inhibitor, suppressed choroidal neovascularization (CNV) in a mouse CNV model in vivo. Together, we show that overexpression of PDGF-D increased pro-angiogenic immunoproteasome activities, and inhibiting immunoproteasome pathway may have therapeutic value for the treatment of neovascular diseases.
Insights
Platelet-derived growth factor-D (PDGF-D) in eye diseases enhances immunoproteasome activity and cell interactions in retinal pigment epithelial (RPE) cells. Inhibiting this pathway may treat neovascular diseases.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Platelet-derived growth factor-D (PDGF-D) is prevalent in ocular diseases.
- Its specific role in ocular cell function and interaction remains unclear.
Purpose of the Study:
- To investigate the impact of PDGF-D on retinal pigment epithelial (RPE) cells and ocular tissues.
- To explore the therapeutic potential of targeting the PDGF-D pathway in neovascular eye diseases.
Main Methods:
- Utilized single-cell RNA sequencing (scRNA-seq) in a mouse model with PDGF-D overexpression in RPE cells.
- Analyzed ligand-receptor interactions and cell-cell communication.
- Administered an immunoproteasome inhibitor (ONX-0914) in a mouse model of choroidal neovascularization (CNV).
Main Results:
- PDGF-D overexpression upregulated immunoproteasome genes in RPE cells, enhancing antigen processing and presentation.
- Significant increase in ligand-receptor pairs indicated heightened cell-cell interactions.
- Detected a novel cell population suggesting PDGF-D-induced RPE epithelial-mesenchymal transition.
- ONX-0914 treatment suppressed choroidal neovascularization in vivo.
Conclusions:
- PDGF-D overexpression promotes pro-angiogenic immunoproteasome activity and alters RPE cell behavior.
- Targeting the immunoproteasome pathway presents a potential therapeutic strategy for neovascular eye conditions.
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