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The P300/XBP1s/Herpud1 axis promotes macrophage M2 polarization and the development of choroidal neovascularization
Wendie Li1, Ying Wang2, Linling Zhu3
1Department of Ophthalmology, Ningbo Eye Hospital, Ningbo, China.
Abstract:
Neovascular age-related macular degeneration (AMD), which is characterized by choroidal neovascularization (CNV), leads to vision loss. M2 macrophages produce vascular endothelial growth factor (VEGF), which aggravates CNV formation. The histone acetyltransferase p300 enhances the stability of spliced X-box binding protein 1 (XBP1s) and promotes the transcriptional activity of the XBP1s target gene homocysteine inducible endoplasmic reticulum protein with ubiquitin-like domain 1 (Herpud1). Herpud1 promotes the M2 polarization of macrophages. This study aimed to explore the roles of the p300/XBP1s/Herpud1 axis in the polarization of macrophages and the pathogenesis of CNV. Hypoxia-induced p300 interacted with XBP1s to acetylate XBP1s in RAW264.7 cells. Additionally, hypoxia-induced p300 enhanced the XBP-1s-mediated unfolded protein response (UPR), alleviated the proteasome-dependent degradation of XBP1s and enhanced the transcriptional activity of XBP1s for Herpud1. The hypoxia-induced p300/XBP1s/Herpud1 axis facilitated RAW264.7 cell M2 polarization. Knockdown of the p300/XBP1s/Herpud1 axis in RAW264.7 cells inhibited the proliferation, migration and tube formation of mouse choroidal endothelial cells (MCECs). The p300/XBP1s/Herpud1 axis increased in infiltrating M2-type macrophages in mouse laser-induced CNV lesions. Blockade of the p300/XBP1s/Herpud1 axis inhibited macrophage M2 polarization and alleviated CNV lesions. Our study demonstrated that the p300/XBP1s/Herpud1 axis in infiltrating macrophages increased the M2 polarization of macrophages and the development of CNV.
Insights
The p300/XBP1s/Herpud1 pathway drives M2 macrophage polarization, worsening neovascular age-related macular degeneration (AMD) and choroidal neovascularization (CNV). Blocking this axis reduces M2 polarization and alleviates CNV development.
Area of Science:
- Ophthalmology
- Immunology
- Molecular Biology
Background:
- Neovascular age-related macular degeneration (AMD) involves choroidal neovascularization (CNV), often exacerbated by M2 macrophages producing vascular endothelial growth factor (VEGF).
- The histone acetyltransferase p300 stabilizes spliced X-box binding protein 1 (XBP1s), enhancing its target gene, Herpud1, which promotes M2 macrophage polarization.
Purpose of the Study:
- To investigate the role of the p300/XBP1s/Herpud1 axis in macrophage polarization and CNV pathogenesis.
- To determine if targeting this axis can mitigate CNV development.
Main Methods:
- Utilized RAW264.7 cells and mouse models of laser-induced CNV.
- Investigated the interaction between hypoxia-induced p300 and XBP1s, including acetylation and degradation.
- Assessed the impact of the p300/XBP1s/Herpud1 axis on M2 polarization and choroidal endothelial cell function.
- Examined the axis expression in CNV lesions and the effect of its blockade.
Main Results:
- Hypoxia-induced p300 acetylates XBP1s, enhancing the unfolded protein response (UPR) and promoting M2 polarization via Herpud1.
- Knockdown of the p300/XBP1s/Herpud1 axis inhibited M2 polarization and reduced choroidal endothelial cell proliferation, migration, and tube formation.
- The p300/XBP1s/Herpud1 axis was upregulated in M2 macrophages within CNV lesions.
- Blocking this axis decreased M2 polarization and alleviated CNV severity.
Conclusions:
- The p300/XBP1s/Herpud1 axis is a key regulator of M2 macrophage polarization.
- This axis plays a significant role in the pathogenesis of CNV.
- Targeting the p300/XBP1s/Herpud1 axis presents a potential therapeutic strategy for AMD.
