PURPOSE: We examined the effect of aging on Fas ligand (FasL) function in a mouse model of choroidal neovascularization (CNV). METHODS: Young and aged mice were laser treated to induce CNV. Bone marrow chimeras were performed between young and aged mice. FasL protein expression was examined in the eye and soluble FasL (sFasL) was measured in the blood. Young and aged mice were treated with a matrix metalloprotease (MMP) inhibitor and systemic sFasL was neutralized by antibody treatment. Macrophages from young and aged mice were tested for sFasL-mediated cytokine production and migration. RESULTS: The elevated CNV response observed with aging was dependent on bone marrow-derived cells. FasL expression in the eye was increased with age, but decreased following laser treatment. Aged mice had higher levels of sFasL in the blood compared to young mice. Systemic treatment with an MMP inhibitor decreased bloodborne sFasL, and reduced CNV in young and aged mice. Systemic neutralization of sFasL reduced CNV only in aged mice. sFasL increased cytokine production in aged macrophages and proangiogenic M2 macrophages. Aged M2 macrophages had elevated Fas (CD95) expression and displayed increased migration in response to sFasL compared to M1 macrophages derived from young animals. CONCLUSIONS: Age modulates FasL function where increased MMP cleavage leads to a loss of function in the eye. The released form of FasL (sFasL) preferentially induces the migration of proangiogenic M2 macrophages into the laser lesions and increases proangiogenic cytokines promoting CNV. FasL may be a viable target for therapeutic intervention in aged-related neovascular disease.
PURPOSE: We examined the effect of aging on Fas ligand (FasL) function in a mouse model of choroidal neovascularization (CNV). METHODS: Young and aged mice were laser treated to induce CNV. Bone marrow chimeras were performed between young and aged mice. FasL protein expression was examined in the eye and soluble FasL (sFasL) was measured in the blood. Young and aged mice were treated with a matrix metalloprotease (MMP) inhibitor and systemic sFasL was neutralized by antibody treatment. Macrophages from young and aged mice were tested for sFasL-mediated cytokine production and migration. RESULTS: The elevated CNV response observed with aging was dependent on bone marrow-derived cells. FasL expression in the eye was increased with age, but decreased following laser treatment. Aged mice had higher levels of sFasL in the blood compared to young mice. Systemic treatment with an MMP inhibitor decreased bloodborne sFasL, and reduced CNV in young and aged mice. Systemic neutralization of sFasL reduced CNV only in aged mice. sFasL increased cytokine production in aged macrophages and proangiogenic M2 macrophages. Aged M2 macrophages had elevated Fas (CD95) expression and displayed increased migration in response to sFasL compared to M1 macrophages derived from young animals. CONCLUSIONS: Age modulates FasL function where increased MMP cleavage leads to a loss of function in the eye. The released form of FasL (sFasL) preferentially induces the migration of proangiogenic M2 macrophages into the laser lesions and increases proangiogenic cytokines promoting CNV. FasL may be a viable target for therapeutic intervention in aged-related neovascular disease.
Authors: Meredith S Gregory; Caroline G Hackett; Emma F Abernathy; Karen S Lee; Rebecca R Saff; Andreas M Hohlbaum; Krishna-Sulayman L Moody; Maura W Hobson; Alexander Jones; Paraskevi Kolovou; Saoussen Karray; Andrea Giani; Simon W M John; Dong Feng Chen; Ann Marshak-Rothstein; Bruce R Ksander Journal: PLoS One Date: 2011-03-29 Impact factor: 3.240
Authors: Helen Vester; Markus S Huber-Lang; Qerim Kida; Alexander Scola; Martijn van Griensven; Florian Gebhard; Andreas K Nüssler; Mario Perl Journal: Immun Ageing Date: 2014-12-11 Impact factor: 6.400
Authors: Anu Kauppinen; Jussi J Paterno; Janusz Blasiak; Antero Salminen; Kai Kaarniranta Journal: Cell Mol Life Sci Date: 2016-02-06 Impact factor: 9.261