2. Academic Validation
  3. Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes

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

  • Nat Commun. 2025 Mar 22;16(1):2821. doi: 10.1038/s41467-025-58074-0.
Kai He # 1,  Xue Dong # 1 2,  Tianjing Yang # 3,  Ziqi Li 1,  Yuming Liu 1,  Jing He 4,  Meng Wu 1 2,  Selena Wei-Zhang 1,  Parhat Kaysar 1,  Bohao Cui 1,  Xueming Yao 3,  Li Zhang 5,  Wei Zhou 1,  Heping Xu 6,  Jun Wei 7,  Qiang Liu 8,  Junhao Hu 9,  Xiaohong Wang 10 11,  Hua Yan 12 13
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Institute of Eye Health and Eye Diseases, China-UK "Belt and Road" Ophthalmology Joint Laboratory, State Key Laboratory of Experimental Hematology, Tianjin Medical University General Hospital, Tianjin, China.
  • 2 Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences; Tianjin Medical University, Tianjin, China.
  • 3 School of Medicine, Nankai University, Tianjin, China.
  • 4 Laboratory of Vascular Biology and Organ Homeostasis, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 5 Department of Ophthalmology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 6 The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
  • 7 Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
  • 8 Department of Neurology, Tianjin Neurological Institute, Tianjin Institute of Immunology, Tianjin Medical University General Hospital, Tianjin, China.
  • 9 Laboratory of Vascular Biology and Organ Homeostasis, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. jhhu@sioc.ac.cn.
  • 10 Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Institute of Eye Health and Eye Diseases, China-UK "Belt and Road" Ophthalmology Joint Laboratory, State Key Laboratory of Experimental Hematology, Tianjin Medical University General Hospital, Tianjin, China. xiaohongwang@tmu.edu.cn.
  • 11 Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences; Tianjin Medical University, Tianjin, China. xiaohongwang@tmu.edu.cn.
  • 12 Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Institute of Eye Health and Eye Diseases, China-UK "Belt and Road" Ophthalmology Joint Laboratory, State Key Laboratory of Experimental Hematology, Tianjin Medical University General Hospital, Tianjin, China. zyyyanhua@tmu.edu.cn.
  • 13 School of Medicine, Nankai University, Tianjin, China. zyyyanhua@tmu.edu.cn.
  • # Contributed equally.
PMID: 40121188 DOI: 10.1038/s41467-025-58074-0
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.

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