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Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes

Author

Listed:
  • Kai He

    (Tianjin Medical University General Hospital)

  • Xue Dong

    (Tianjin Medical University General Hospital
    School of Basic Medical Sciences; Tianjin Medical University)

  • Tianjing Yang

    (Nankai University)

  • Ziqi Li

    (Tianjin Medical University General Hospital)

  • Yuming Liu

    (Tianjin Medical University General Hospital)

  • Jing He

    (Chinese Academy of Sciences)

  • Meng Wu

    (Tianjin Medical University General Hospital
    School of Basic Medical Sciences; Tianjin Medical University)

  • Selena Wei-Zhang

    (Tianjin Medical University General Hospital)

  • Parhat Kaysar

    (Tianjin Medical University General Hospital)

  • Bohao Cui

    (Tianjin Medical University General Hospital)

  • Xueming Yao

    (Nankai University)

  • Li Zhang

    (The Second Affiliated Hospital of Chongqing Medical University)

  • Wei Zhou

    (Tianjin Medical University General Hospital)

  • Heping Xu

    (Queen’s University Belfast)

  • Jun Wei

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Qiang Liu

    (Tianjin Medical University General Hospital)

  • Junhao Hu

    (Chinese Academy of Sciences)

  • Xiaohong Wang

    (Tianjin Medical University General Hospital
    School of Basic Medical Sciences; Tianjin Medical University)

  • Hua Yan

    (Tianjin Medical University General Hospital
    Nankai University)

Abstract

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+ 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.

Suggested Citation

  • Kai He & Xue Dong & Tianjing Yang & Ziqi Li & Yuming Liu & Jing He & Meng Wu & Selena Wei-Zhang & Parhat Kaysar & Bohao Cui & Xueming Yao & Li Zhang & Wei Zhou & Heping Xu & Jun Wei & Qiang Liu & Junh, 2025. "Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes," Nature Communications, Nature, vol. 16(1), pages 1-25, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58074-0
    DOI: 10.1038/s41467-025-58074-0
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