Photoreceptor Proteins Initiate Microglial Activation via Toll-like Receptor 4 in Retinal Degeneration Mediated by All-trans-retinal

被引：154

作者：

Kohno, Hideo ^{[1
]}

Chen, Yu ^{[1
]}

Kevany, Brian M. ^{[1
]}

Pearlman, Eric ^{[2
]}

Miyagi, Masaru ^{[1
,2
,3
]}

Maeda, Tadao ^{[1
,2
]}

Palczewski, Krzysztof ^{[1
]}

Maeda, Akiko ^{[1
,2
]}

机构：

[1] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Dept Ophthalmol & Visual Sci, Cleveland, OH 44106 USA

[3] Case Western Reserve Univ, Ctr Prote, Cleveland, OH 44106 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2013年 / 288卷 / 21期

基金：

美国国家卫生研究院;

关键词：

MACULAR DEGENERATION; OXIDATIVE STRESS; MOUSE RETINA; EXTRACELLULAR HSP70; PIGMENT EPITHELIUM; ENDOGENOUS LIGANDS; APOPTOTIC CELLS; MICE; INFLAMMATION; DISEASE;

D O I：

10.1074/jbc.M112.448712

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 wildtype 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.

引用

页码：15326 / 15341

页数：16

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