Role of fas-ligand in age-related maculopathy not established

Lambooij, A. C.; Kliffen, Mike; Mooy, Cornelia M.; Kuijpers, Robert W A M

doi:10.1016/s0002-9394(01)01011-x

Cited by 7 publications

(4 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reduced angiogenesis correlated with increased FasL expression on choroidal tissue and decreased sFasL in the serum and eye as measured by ELISA, consistent with the notion that blockade of mFasL cleavage led to increased expression of pro-apoptotic mFasL, and more effective elimination of Fas+ infiltrating vascular endothelial cells [15]. In apparent contrast to this premise, examination of surgically excised choroidal neovascular membranes from patients diagnosed with "wet" AMD did not find a correlation between the expression of mFasL on RPE cells and either the size of neovascular membranes, or apoptosis of choroidal endothelial cells [32,33]. One important problem in the in vivo analysis of sFasL and mFasL function is the difficulty of specifically regulating FasL cleavage.…”

Section: Introductionsupporting

confidence: 73%

Fas Ligand enhances vessel maturation and inhibits vascular leakage associated with age-related macular degeneration

Koirala,

Marshak-Rothstein,

Ksander

et al. 2024

Preprint

View full text Add to dashboard Cite

Neovascular age-related macular degeneration (AMD), results from choroidal neovascularization (CNV), retinal edema and loss of photoreceptors. Previous studies suggested that Fas Ligand (FasL) on retinal pigment epithelial cells inhibited CNV by inducing apoptosis of infiltrating Fas + vascular endothelial cells. However, induction of apoptosis depends on membrane-bound (mFasL) while the FasL cleavage product (sFasL) is neuroprotective. To better understand how FasL regulates the development of CNV, we used a mouse model of laser CNV to evaluate the development of CNV in mice with a FasL cleavage site mutation (ΔCS) and can only express the membrane-bound form of FasL. There was no significant difference in CNV size and area of vascular leakage in homozygous FasLΔCS/ΔCS mice when compared to wild type mice. Unexpectedly, heterozygous FasLΔCS/WT mice developed significantly less vascular leakage and showed accelerated neovessel maturation. However, CNV was not prevented in heterozygous FasLΔCS/WT mice if the Fas receptor was deleted in myeloid cells (FasLΔCS/+ Fasflox/flox CreLysM). Thus, FasL-mediated CNV inhibition depends on the extent of FasL cleavage, and on FasL engagement of Fas + myeloid cells. Moreover, accelerated neovessel maturation prevents vascular leakage in AMD.

show abstract

Section: Introductionsupporting

confidence: 73%

Fas Ligand enhances vessel maturation and inhibits vascular leakage associated with age-related macular degeneration

Koirala,

Marshak-Rothstein,

Ksander

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Reduced angiogenesis correlated with increased FasL expression on choroidal tissue and decreased sFasL in the serum and eye as measured by ELISA, consistent with the idea that inhibition of mFasL cleavage led to increased expression of proapoptotic mFasL, and more effective elimination of Fas+ infiltrating vascular endothelial cells 137 . However, examination of surgically excised choroidal neovascular membranes from patients diagnosed with “wet” AMD did not find a correlation between the expression of mFasL on RPE cells and either the size of neovascular membranes, or apoptosis of choroidal endothelial cells 143,144 . One important problem in the in vivo analysis of sFasL and mFasL function is the difficulty of specifically regulating FasL cleavage.…”

Section: Fasl In Ocular Pathologysupporting

confidence: 67%

The FasLane to ocular pathology—metalloproteinase cleavage of membrane-bound FasL determines FasL function

Gregory-Ksander

Marshak‐Rothstein

2021

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Fas ligand (FasL) is best known for its ability to induce cell death in a wide range of Fas‐expressing targets and to limit inflammation in immunoprivileged sites such as the eye. In addition, the ability of FasL to induce a much more extensive list of outcomes is being increasingly explored and accepted. These outcomes include the induction of proinflammatory cytokine production, T cell activation, and cell motility. However, the distinct and opposing functions of membrane‐associated FasL (mFasL) and the C‐terminal soluble FasL fragment (sFasL) released by metalloproteinase cleavage is less well documented and understood. Both mFasL and sFasL can form trimers that engage the trimeric Fas receptor, but only mFasL can form a multimeric complex in lipid rafts to trigger apoptosis and inflammation. By contrast, a number of reports have now documented the anti‐apoptotic and anti‐inflammatory activity of sFasL, pointing to a critical regulatory function of the soluble molecule. The immunomodulatory activity of FasL is particularly evident in ocular pathology where elimination of the metalloproteinase cleavage site and the ensuing increased expression of mFasL can severely exacerbate the extent of inflammation and cell death. By contrast, both homeostatic and increased expression of sFasL can limit inflammation and cell death. The mechanism(s) responsible for the protective activity of sFasL are discussed but remain controversial. Nevertheless, it will be important to consider therapeutic applications of sFasL for the treatment of ocular diseases such as glaucoma.

show abstract

“…Endogenous expression and exogenous application of TGF-β1 induced both capillary formation and apoptosis in glomerular EC in culture, and both apoptosis and capillary formation were uniformly and entirely absent in EC transfected with a decoy TGF-β receptor [80]. Moreover, the apoptotic Fas/Fas ligand (CD95) system was believed to control angiogenesis beneath the retina [81] in some models but not in others [82], possible due to a non-apoptotic mechanism of action [83]. In fact, the engagement of Fas receptor with the agonist anti-Fas antibody Jo2 was shown to stimulate angiogenesis in an in vivo Matrigel assay [84].…”

Section: Induction Of Ec Apoptosis By Mphmentioning

confidence: 99%