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Franziska Fischer, Peter Wieghofer, Jana Koch, Johannes Baumann, Marc Leinweber, Yannik Laich, Pei pei Zhang, Gunther R Schlunck, Hansjürgen Agostini, Marco Prinz, Clemens Lange; The role of the Interferon Regulatory Factor 8 for retinal tissue homeostasis and development of choroidal neovascularisation. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2243.
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© 2017 Association for Research in Vision and Ophthalmology.
Retinal microglia (MG) have been implicated in tissue homeostasis, neurovascular development and the formation of choroidal neovascularization (CNV) in patients with age-related macular degeneration. The Interferon Regulatory Factor 8 (IRF8) is a central transcription factor in myeloid cell maturation, differentiation and lineage commitment. The aim of this study was to determine the role of IRF8 for retinal MG development, neurovascular homeostasis and the formation of laser-induced CNV.
Irf8-/- Cx3cr1+/GFP mice (IRF8 KO, n=6) and age-matched Cx3cr1+/GFP controls (IRF8 WT, n=6) were assessed for MG morphology by immunohistochemistry. The expression of factors involved in homeostasis and clearance of apoptotic cells, including CD14, CD64, CX3CR1 and F4/80 was determined in MG of IRF8 KO and WT mice by flow-cytometry. MG distribution was analyzed during development at postnatal days (P1, P7, P14; n=5) and in adult mice (n=5). The vascular phenotype and the retinal function of IRF8 KO mice were assessed by immunohistochemistry and electroretinography (ERG) respectively. Finally, the role of IRF8 for CNV was analyzed in the laser-induced CNV model.
Deficiency of IRF8 was associated with a severely altered MG morphology in adult IRF8 KO compared to IRF8 WT mice. Flow-cytometry analysis of MG cells revealed a downregulation of CD64 (p<0.001) and CX3CR1 (p=0.03) as well as an upregulaton of CD14 (p<0.01) and F4/80 (p=0.05) in adult IRF8 KO mice indicating a disturbed cellular homeostasis. The number and distribution of retinal MG were altered in IRF8 KO mice, specifically in both, the developing and mature outer plexiform layers (OPL), but not in the inner plexiform layer (IPL) of adult mice. The retinal vasculature and neuroretinal function were similar in adult IRF8 KO and WT animals. In the laser-induced CNV model IRF8 deficient mice exhibited reduced myeloid cell recruitment to sites of laser injury (p<0.01) and increased size of CNV (p=0.03) as compared to WT controls.
Our study demonstrates that IRF8 is vital for MG homeostasis and function but not for retinal neurovascular development. After tissue injury IRF8 is a critical factor for transforming MG into a reactive phenotype thereby modulating retinal inflammation and the formation of CNV.
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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