Abstract
Although several genetic and biochemical factors are associated with the pathogenesis of retinal degeneration, it has yet to be determined how these different impairments can cause similar degenerative phenotypes. Here, we report microglial/macrophage activation in both a Stargardt disease and age-related macular degeneration mouse model caused by delayed clearance of all-trans-retinal from the retina, and in a retinitis pigmentosa mouse model with impaired retinal pigment epithelium (RPE) phagocytosis. Mouse microglia displayed RPE cytotoxicity and increased production of inflammatory chemokines/cytokines, Ccl2, Il1b, and Tnf, after coincubation with ligands that activate innate immunity. Notably, phagocytosis of photoreceptor proteins increased the activation of microglia/macrophages and RPE cells isolated from model mice as well as wild-type mice. The mRNA levels of Tlr2 and Tlr4, which can recognize proteins as their ligands, were elevated in mice with retinal degeneration. Bone marrow-derived macrophages from Tlr4-deficient mice did not increase Ccl2 after coincubation with photoreceptor proteins. Tlr4(-/-)Abca4(-/-)Rdh8(-/-) mice displayed milder retinal degenerative phenotypes than Abca4(-/-)Rdh8(-/-) mice. Additionally, inactivation of microglia/macrophages by pharmacological approaches attenuated mouse retinal degeneration. This study demonstrates an important contribution of TLR4-mediated microglial activation by endogenous photoreceptor proteins in retinal inflammation that aggravates retinal cell death. This pathway is likely to represent an underlying common pathology in degenerative retinal disorders.
Highlights
The host inflammatory response can contribute to the pathogenesis of retinal degeneration
To identify additional retinal degenerative symptoms associated with light-induced photoreceptor death, 4-week-old Abca4Ϫ/ϪRdh8Ϫ/Ϫ mice were exposed to light at 10,000 lux for 30 min, and in vivo Scanning Laser Ophthalmoscopy (SLO) imaging was performed
AF spots and infiltrated cells appeared similar in size, and these cells were stained with Abs for Iba-1, a microglia marker and F4/80, a macrophage marker (Fig. 1B)
Summary
The host inflammatory response can contribute to the pathogenesis of retinal degeneration. This study demonstrates an important contribution of TLR4-mediated microglial activation by endogenous photoreceptor proteins in retinal inflammation that aggravates retinal cell death This pathway is likely to represent an underlying common pathology in degenerative retinal disorders. The Abca4Ϫ/ϪRdh8Ϫ/Ϫ mouse features an AMD-like retinal phenotype that includes lipofuscin accumulation, drusen formation, and photoreceptor/RPE atrophy followed by choroidal neovascularization [16]. This phenotype is exacerbated by light exposure, which causes acute retinal degeneration [17]. Tlr deficiency and microglial inactivation by minocycline attenuated retinal degeneration in Abca4Ϫ/ϪRdh8Ϫ/Ϫ mice These observations indicate that microglial activation by endogenous retinal proteins arising from injured photoreceptors plays an important role in the pathogenesis of retinal degeneration
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