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

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; Junhao Hu; Xiaohong Wang; Hua Yan

doi:10.1038/s41467-025-58074-0

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

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, Junhao Hu, Xiaohong Wang, Hua Yan

Research output: Contribution to journal › Article › peer-review

1 Downloads (Pure)

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.

Original language	English
Article number	2821
Journal	Nature Communications
Volume	16
DOIs	https://doi.org/10.1038/s41467-025-58074-0
Publication status	Published - 22 Mar 2025

Bibliographical note

Keywords

Semaphorins/metabolism
Animals
Pericytes/metabolism
Humans
Macular Degeneration/metabolism
Mice
Receptors, Cell Surface/metabolism
Nerve Tissue Proteins/metabolism
Choroidal Neovascularization/metabolism
CD8-Positive T-Lymphocytes/immunology
Male
Mice, Inbred C57BL
Chemokine CXCL12/metabolism
Female
Disease Models, Animal
Smoking/adverse effects
Antigens, CD/metabolism
Receptors, CXCR4/metabolism
Phosphorylation
Signal Transduction

Access to Document

10.1038/s41467-025-58074-0Licence: CC BY-NC-ND

Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes
Copyright 2025 the authors. This is an open access article published under a Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 6.47 MBLicence: CC BY-NC-ND

Cite this

He, K., Dong, X., Yang, T., Li, Z., Liu, Y., He, J., Wu, M., Wei-Zhang, S., Kaysar, P., Cui, B., Yao, X., Zhang, L., Zhou, W., Xu, H., Wei, J., Liu, Q., Hu, J., Wang, X., & Yan, H. (2025). Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes. Nature Communications, 16, Article 2821. https://doi.org/10.1038/s41467-025-58074-0

@article{9c81c57b65d24a978ce279af12519159,

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

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. ",

keywords = "Semaphorins/metabolism, Animals, Pericytes/metabolism, Humans, Macular Degeneration/metabolism, Mice, Receptors, Cell Surface/metabolism, Nerve Tissue Proteins/metabolism, Choroidal Neovascularization/metabolism, CD8-Positive T-Lymphocytes/immunology, Male, Mice, Inbred C57BL, Chemokine CXCL12/metabolism, Female, Disease Models, Animal, Smoking/adverse effects, Antigens, CD/metabolism, Receptors, CXCR4/metabolism, Phosphorylation, Signal Transduction",

author = "Kai He and Xue Dong and Tianjing Yang and Ziqi Li and Yuming Liu and Jing He and Meng Wu and Selena Wei-Zhang and Parhat Kaysar and Bohao Cui and Xueming Yao and Li Zhang and Wei Zhou and Heping Xu and Jun Wei and Qiang Liu and Junhao Hu and Xiaohong Wang and Hua Yan",

note = "{\textcopyright} 2025. The Author(s).",

year = "2025",

month = mar,

day = "22",

doi = "10.1038/s41467-025-58074-0",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

He, K, Dong, X, Yang, T, Li, Z, Liu, Y, He, J, Wu, M, Wei-Zhang, S, Kaysar, P, Cui, B, Yao, X, Zhang, L, Zhou, W, Xu, H, Wei, J, Liu, Q, Hu, J, Wang, X & Yan, H 2025, 'Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes', Nature Communications, vol. 16, 2821. https://doi.org/10.1038/s41467-025-58074-0

TY - JOUR

T1 - Smoking aggravates neovascular age-related macular degeneration via Sema4D-PlexinB1 axis-mediated activation of pericytes

AU - He, Kai

AU - Dong, Xue

AU - Yang, Tianjing

AU - Li, Ziqi

AU - Liu, Yuming

AU - He, Jing

AU - Wu, Meng

AU - Wei-Zhang, Selena

AU - Kaysar, Parhat

AU - Cui, Bohao

AU - Yao, Xueming

AU - Zhang, Li

AU - Zhou, Wei

AU - Xu, Heping

AU - Wei, Jun

AU - Liu, Qiang

AU - Hu, Junhao

AU - Wang, Xiaohong

AU - Yan, Hua

PY - 2025/3/22

Y1 - 2025/3/22

N2 - 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.

AB - 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.

KW - Semaphorins/metabolism

KW - Animals

KW - Pericytes/metabolism

KW - Humans

KW - Macular Degeneration/metabolism

KW - Mice

KW - Receptors, Cell Surface/metabolism

KW - Nerve Tissue Proteins/metabolism

KW - Choroidal Neovascularization/metabolism

KW - CD8-Positive T-Lymphocytes/immunology

KW - Male

KW - Mice, Inbred C57BL

KW - Chemokine CXCL12/metabolism

KW - Female

KW - Disease Models, Animal

KW - Smoking/adverse effects

KW - Antigens, CD/metabolism

KW - Receptors, CXCR4/metabolism

KW - Phosphorylation

KW - Signal Transduction

U2 - 10.1038/s41467-025-58074-0

DO - 10.1038/s41467-025-58074-0

M3 - Article

C2 - 40121188

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

M1 - 2821

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this