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Xiaowei Sun, Yan Liu, Zijing Huang, Tian Zhou, Xiaowei Zhu, Mei Li, Bing Cheng, Chang He, Xialin Liu; Microglia Phenotypic Switching from M1 to M2 as a Novel Target for Suppressing Retinal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2571. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Microglia, a special type of immune cells in retina, is also implicated in retinal vasculature. However, the role and mechanism of microglia in pathological neovascularization are unclear. This study was to explore the activation profiles of retinal microglia in oxygen-induced retinopathy (OIR) model, and to evaluated whether α1-antitrypsin (AAT), a new immunomodulation drug, could alter microglia polarization and suppress retinal angiogenesis.
OIR was established in C57BL/6 mice and received LPS, IL-4, AAT by intravitreal injection at P12, respectively. At the peak of angiogenesis at P17, retinae were collected and prepared for further investigation. Microglia phenotype (NOS2, Arg1, CD86, CD206, etc) and relevant cytokines were evaluated by flow cytometry, qPCR, Western blot and immunofluorescent (IF) staining. The retinal neovascularization was assessed by IB4 staining and histology.
Almost all activated Iba-1+ microglia surrounded the pathological neovascular tufts were double-immunolabeling with NOS2 (M1 marker), while hardly Arg1(M2 marker) was observed in OIR retinae at P17. Flow cytometry results also showed that increased level of CD11b+ CD45int microglia in the OIR retinae. Importantly, LPS injection induced M1 microglia and accelerated angiogenesis, whereas IL-4 injection promoted M2 polarization and suppressed neovascularization. In addition, AAT treatment remarkably inhibited the presence of iNOS+Iba-1+ M1-microglia while promoted M2-associated marker Arg1 expression in Iba-1+ microglia, suppressed pro-inflammatory and pro-angiogenic cytokines (IL-6, CCL2, TNFα and VEGF), and inhibited pathological angiogenesis.
Our findings uncover a novel mechanism that pro-inflammatory M1 phenotype of microglia contributed to retinal neovascularization in OIR model. AAT suppressed neovascularization through modulating microglia polarization toward M2 and away M1 phenotype, which may be novel therapeutic interventions for angiogenic diseases.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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