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  3. Unveiling the choroidal immune landscape revealed interferon-gamma and TNF-alpha as novel therapeutic targets in dry AMD

Unveiling the choroidal immune landscape revealed interferon-gamma and TNF-alpha as novel therapeutic targets in dry AMD

  • Sci China Life Sci. 2025 Oct 10. doi: 10.1007/s11427-025-2951-5.
Lin Ye 1 2,  Tujing Zhao 1 2,  Huaping Tian 1,  Runze Li 1,  Zheng Li 1,  Hongjing Li 1,  Ruilin Liao 1,  Junlan Chuan 1 2,  Haojue Xu 3,  Liang Zou 4,  Chao Qu 5,  Yi Shi 1,  Zhenglin Yang 6 7 8,  Lulin Huang 9 10
Affiliations

Affiliations

  • 1 Genetic Diseases Key Laboratory of Sichuan Province, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China.
  • 2 Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610075, China.
  • 3 Sichuan-Chongqing Joint Key Laboratory for Pathology and Laboratory Medicine, Jinfeng Laboratory, Chongqing, 401329, China.
  • 4 School of Food and Biological Engineering, Chengdu University, Chengdu, 610106, China.
  • 5 Department of Ophthalmology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610075, China.
  • 6 Genetic Diseases Key Laboratory of Sichuan Province, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China. yangzhenglin@cashq.ac.cn.
  • 7 Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610075, China. yangzhenglin@cashq.ac.cn.
  • 8 Sichuan-Chongqing Joint Key Laboratory for Pathology and Laboratory Medicine, Jinfeng Laboratory, Chongqing, 401329, China. yangzhenglin@cashq.ac.cn.
  • 9 Genetic Diseases Key Laboratory of Sichuan Province, Department of Laboratory Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610054, China. huangluling@yeah.net.
  • 10 Research Unit for Blindness Prevention, Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, 610075, China. huangluling@yeah.net.
PMID: 41077603 DOI: 10.1007/s11427-025-2951-5
Abstract

Age-related macular degeneration (AMD), particularly its atrophic (dry) form, is a leading cause of irreversible blindness in the elderly. Limited treatment efficacy stems from its complex pathogenesis, highlighting an urgent need for novel therapeutic targets. This study investigates the contribution of the choroidal immune microenvironment, focusing on intercellular communication involving resident fibroblasts-a cell type whose role in AMD remains poorly defined. By analyzing single-cell RNA Sequencing data from human choroid, we interrogated crosstalk between fibroblasts, macrophages, and NK/T cells, identifying interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) signaling pathways as central mediators. We demonstrate that activated choroidal fibroblasts release key inflammatory mediators, including IL6, CCL2, CSF1, CXCL9, and CXCL10, which functionally recruit macrophages and CD8+ T cells, thereby shaping the local immune landscape. Critically, targeting these pathways in vivo using TAPI-1 (inhibiting TNFα processing) and Tofacitinib (inhibiting IFNγ signaling) significantly ameliorated retinal, RPE, and choroidal pathology in a NaIO3-induced murine model of dry AMD. Our findings underscore the pathogenic role of fibroblast-mediated choroidal inflammation driven by TNFα and IFNγ signaling in dry AMD, presenting these pathways as promising therapeutic targets.

Keywords

IFNγ; TAPI-1; TNFα; Tofacitinib; fibroblasts.

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