{
  "abstract": "Introduction: Age-related macular degeneration (AMD), results from choroidal neovascularization (CNV), retinal edema and loss of photoreceptors. Previous studies suggest that Fas Ligand (FasL) on retinal pigment epithelial cells inhibits CNV by inducing apoptosis of infiltrating Fas+ vascular endothelial cells. However, membrane-bound FasL (mFasL) can be cleaved by metalloproteinases to release a soluble fragment (sFasL) and the two isoforms have distinct functions. mFasL induces apoptosis and inflammation while sFasL has been shown to promote cell activation, cell survival, cell proliferation, and cell migration. In this current study, we use a genetic approach to prevent cleavage of mFasL in order to determine the extent to which sFasL and/or mFasL contribute to vascular leakage in a mouse model of laser-induced CNV.\n\nMethods: To distinguish the role of mFasL from sFasL in regulating CNV and vascular leakage, we used a 532 nm laser to induce CNV in three types of mice: (i) wild-type (WT) FasL WT/WT mice that express low levels of mFasL and high levels of sFasL, (ii) homozygous FasL ΔCS/ΔCS mice that express greater than normal levels of mFasL and no sFasL, and (iii) heterozygous FasL ΔCS/WT mice that express greater than normal levels of mFasL and less than normal levels of sFasL.\n\nResults: Unexpectedly, CNV size and the area of vascular leakage were comparable in homozygous FasL ΔCS/ΔCS and WT mice. However, heterozygous FasL ΔCS/WT mice developed significantly less vascular leakage and showed accelerated neovessel maturation that depended on the expression of the Fas receptor in LysM-positive myeloid cells. Moreover, the protective phenotype observed in heterozygous FasL ΔCS/WT mice correlated with increased retinal expression of PDGFRb and TGFβ1, reduced retinal expression of VEGFA, and increased expression of PEDF, which is known to inhibit VEGF-induced vascular permeability and promote vessel normalization.\n\nDiscussion: Overall, these data indicate that FasL-mediated protection from CNV depends on expression of both sFasL and mFasL. Moreover, the accelerated neovessel maturation observed in heterozygous FasL ΔCS/WT mice depends on Fas signaling in LysM-positive myeloid cells and is highly dependent on the extent of FasL cleavage, identifying Fas ligand cleavage as a potential therapeutic strategy to promote neovessel maturation and prevent vascular leakage in wet AMD.",
  "abstract_shown": true,
  "affiliations": [
    "Schepens Eye Research Institute of Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School",
    "Department of Medicine, University of Massachusetts (UMass) Chan Medical School"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Adarsha Koirala"
    },
    {
      "affs": [
        1
      ],
      "name": "Ann Marshak-Rothstein"
    },
    {
      "affs": [
        0
      ],
      "name": "Bruce R. Ksander"
    },
    {
      "affs": [
        0
      ],
      "name": "Meredith Gregory-Ksander"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4neyt8wbcjg5k.bib",
  "cited_by": 0,
  "doi": "10.3389/fimmu.2026.1898554",
  "fulltext_url": null,
  "id": "4neyt8wbcjg5k",
  "issns": [
    "1664-3224"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1898554/full",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2731|Retinal Diseases and Treatments"
    ]
  ],
  "openalex": "W4396721669",
  "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1898554/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-22",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/4neyt8wbcjg5k.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:17Z",
      "native_id": "10.3389/fimmu.2026.1898554",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1898554/full"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "issn:1664-3224",
      "subfield": "immunology"
    }
  ],
  "title": "Fas Ligand enhances vessel maturation and inhibits vascular leakage associated with age-related macular degeneration",
  "title_text": "Fas Ligand enhances vessel maturation and inhibits vascular leakage associated with age-related macular degeneration",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:17Z",
  "url": "https://research.draconitic.com/paper/4neyt8wbcjg5k",
  "venue": "Frontiers in Immunology",
  "versions": []
}