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Nadine Reichhart, Sergio Crespo, Norbert Kociok, Olaf Strauss, Antonia Joussen; Role of PlGF in cellular immune response in CNV. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4988.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration (AMD) is a major reason for vision loss mainly due to choroidal neovascularization (CNV). A cellular immune response, driven by mononuclear phagocytes (MP), seems to play a pivotal role in the pathogenesis of AMD. In clinical practice it has been shown that a switch from anti- VEGF-A to a combined anti VEGF+anti Placenta growth factor (PlGF) treatment is beneficial for some patients. Since MP carry VEGFR1 (Flt-1), a receptor specific for both VEGF-A and PlGF, we hypothesize that a regulation of MP activity by PlGF contributes to the pathophysiology of CNV.
Laser-induced CNV was used in MacGreen (Csf1r-EGFP) mice, creating 5 laser spots around the optic nerve (argon laser, 120mW, 50µm, 100ms). MP were visualized in vivo by SLO autofluorescence (AF) and quantified ex vivo in whole-mounts using GFP and Iba-1. Differential expression of angiogenic factors and M1/M2 macrophage polarization markers were analyzed by qPCR. Protein expression of PlGF and VEGF-A was detected both in sagittal sections and whole-mounts of the retina.One day after laser (D1), intravitreal injection of anti-VEGF-A+anti-PlGF (aflibercept) or anti-PlGF was performed and macrophage recruitment was analized. Unspecific IgG served as control.
After CNV, PlGF mRNA expression increases at D1 and declines to normal levels at D4 whereas VEGF-A expression did not increase during the early phase (D1) and even decreased at D4. At D14, in sagittal sections or retina whole-mounts, we observed that up-regulation of VEGF-A expression in response to laser impact is limited to the scar area, while PlGF shows a more homogenous distribution. Additionally, comparable to PlGF expression, activated MP were also present in distant areas from the laser-spots. Among macrophages, we found an increase of M1 markers (CD68 and CD86) up to D4, whereas the M2 marker IL4R did not show significant changes.Intravitreal Injection of aflibercept significantly decreased the amount of activated MP and minimized the size of the laser scar at D7 and D14 respectively, whereas anti PlGF could not suppress the macrophage recruitment effectively. Laser scars in PlGF injected eyes were similar to controls.
Thus we show first hints that the interplay of PlGF and microglia plays an important role in the initial phase of CNV after laser. However, anti-PlGF treatment alone is not sufficient to suppress MP recruitment.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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