Abstract
BackgroundMicroglia cells represent the resident innate immune cells of the retina and are important for retinal development and tissue homeostasis. However, dysfunctional microglia can have a negative impact on the structural and functional integrity of the retina under native and pathological conditions.MethodsIn this study, we examined interferon-regulatory factor 8 (Irf8)–deficient mice to determine the transcriptional profile, morphology, and temporospatial distribution of microglia lacking Irf8 and to explore the effects on retinal development, tissue homeostasis, and formation of choroidal neovascularisation (CNV).ResultsOur study shows that Irf8-deficient MG exhibit a considerable loss of microglial signature genes accompanied by a severely altered MG morphology. An in-depth characterisation by fundus photography, fluorescein angiography, optical coherence tomography and electroretinography revealed no major retinal abnormalities during steady state. However, in the laser-induced CNV model, Irf8-deficient microglia showed an increased activity of biological processes critical for inflammation and cell adhesion and a reduced MG cell density near the lesions, which was associated with significantly increased CNV lesion size.ConclusionsOur results suggest that loss of Irf8 in microglia has negligible effects on retinal homeostasis in the steady state. However, under pathological conditions, Irf8 is crucial for the transformation of resident microglia into a reactive phenotype and thus for the suppression of retinal inflammation and CNV formation.
Highlights
Microglia cells represent the resident innate immune cells of the retina and are important for retinal development and tissue homeostasis
interferon regulatory factor 8 (IRF8) is the most abundantly expressed member of the IRF family in retinal microglia The interferon regulatory factor (IRF) family is critical for the development, maturation and function of myeloid cells [40]
The expression of interferon-regulatory factor 8 (Irf8) in Retinal microglia cells (rMG) exceeded the expression in brain microglia (bMG) and bone marrow (BM) monocytes indicating a distinct function of Irf8 for rMG
Summary
Microglia cells represent the resident innate immune cells of the retina and are important for retinal development and tissue homeostasis. Dysfunctional microglia can have a negative impact on the structural and functional integrity of the retina under native and pathological conditions. Retinal microglia cells (rMG) constitute the resident myeloid cell population in the neuroretina and are critical for retinal development, tissue homeostasis and response to cell damage. RMG interact closely with synapses to maintain synaptic structure and electroretinal function and continuously scan the local environment for danger signals associated with injury or pathogens [56]. In response to tissue damage or infection, rMG rapidly attain an activated phenotype, migrate towards the site of injury and contribute to phagocytosis, inflammation and pathological events [4, 52, 59]. Studies on the role of rMG in the development of CNV, revealed conflicting results, and both detrimental and protective roles of MG for the progression of CNV have been discussed in the past [2, 14, 36, 49, 51]
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