Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes
Age-related macular degeneration (AMD) is a prevalent neuroinflammation condition and the leading cause of irreversible blindness among the elderly population. Smoking significantly increases AMD risk, yet the mechanisms remain unclear. Here, we investigate the role of Sema4D-PlexinB1 axis in the progression of AMD, in which Sema4D-PlexinB1 is highly activated by smoking. Using patient-derived samples and mouse models, we discover that smoking increases the presence of Sema4D on the surface of CD8<sup>+</sup> T cells that migrate into the choroidal neovascularization (CNV) lesion via CXCL12-CXCR4 axis and interact with its receptor PlexinB1 on choroidal pericytes. This leads to ROR2-mediated PlexinB1 phosphorylation and pericyte activation, thereby disrupting vascular homeostasis and promoting neovascularization. Inhibition of Sema4D reduces CNV and improves the benefit of anti-VEGF treatment. In conclusion, this study unveils the molecular mechanisms through which smoking exacerbates AMD pathology, and presents a potential therapeutic strategy by targeting Sema4D to augment current AMD treatments.
Authors
- Xueming Yao (ORCID: https://orcid.org/0000-0002-4677-6686)
- Junhao Hu (ORCID: https://orcid.org/0000-0003-0699-1119)
- Selena Wei-Zhang
- Li Zhang (ORCID: https://orcid.org/0000-0002-9742-0540)
- Heping Xu (ORCID: https://orcid.org/0000-0003-4000-931X)
- Tianjing Yang (ORCID: https://orcid.org/0000-0002-9191-5219)
- Hua Yan (ORCID: https://orcid.org/0000-0002-7651-840X)
- Jun Wei
- Parhat Kaysar
- Jing He
- Qiang Liu (ORCID: https://orcid.org/0000-0002-6621-0591)
- Xiaohong Wang (ORCID: https://orcid.org/0000-0001-8628-243X)
- Ziqi Li (ORCID: https://orcid.org/0000-0002-6345-4347)
- Kai He (ORCID: https://orcid.org/0000-0001-9905-5906)
- Dong Xue (ORCID: https://orcid.org/0000-0002-7269-6356)
- Meng Wu (ORCID: https://orcid.org/0000-0003-2111-2645)
- Wei Zhou (ORCID: https://orcid.org/0000-0002-3224-7046)
- Bohao Cui
- Yuming Liu
Institutions
- Queen's University Belfast (GB)
- Dalian Medical University (CN)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Nankai University (CN)
- Tianjin Medical University General Hospital (CN)
- Second Affiliated Hospital of Chongqing Medical University (CN)
- Shanghai Institute of Organic Chemistry (CN)
- Tianjin Medical University Eye Hospital (CN)
- Institute of Hematology & Blood Diseases Hospital (CN)
- Tianjin Medical University (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-22
- DOI
- https://doi.org/10.1038/s41467-025-58074-0
- Citations
- 12
- Primary Topic
- Axon Guidance and Neuronal Signaling
- Type
- article
- Field-Weighted Citation Impact
- 10.91