Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy.
Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy.
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DOI：
10.1038/s41598-018-25557-8
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发表时间：
2018-05-09
影响因子：
4.6
通讯作者：
van Lookeren Campagne M
中科院分区：
文献类型：
--
作者：
Katschke KJ Jr;Xi H;Cox C;Truong T;Malato Y;Lee WP;McKenzie B;Arceo R;Tao J;Rangell L;Reichelt M;Diehl L;Elstrott J;Weimer RM;van Lookeren Campagne M
地图状萎缩（GA）是干性年龄相关性黄斑变性（AMD）的晚期形式，其特征在于在特征性细胞外沉积物的背景下视网膜色素上皮细胞和光感受器的进行性损失，并且仍然是严重未满足的医疗需求。虽然AMD的遗传易感性由补体基因的多态性主导，但补体激活如何导致视网膜萎缩仍不清楚。在这里，我们表明，补体激活感光细胞外段（POS）在视网膜周边与GA相关的萎缩性病变。当暴露于人血清后，外血视网膜屏障破坏，POS作为有效的激活剂的经典和替代补体途径。在视网膜变性的小鼠模型中，光感受器上的经典和替代途径补体激活导致光感受器功能丧失。这依赖于C5a介导的外周血单核细胞的募集，但独立于驻留的小胶质细胞。需要对经典和替代补体C3和C5转化酶进行遗传或药理学抑制，以减少感光杆和视锥的进行性变性。我们的研究表明，全身经典和替代补体蛋白和外周血单核细胞作为局部视网膜变性的关键效应子，与补体激活对GA的贡献具有潜在相关性。
Geographic atrophy (GA), the advanced form of dry age-related macular degeneration (AMD), is characterized by progressive loss of retinal pigment epithelium cells and photoreceptors in the setting of characteristic extracellular deposits and remains a serious unmet medical need. While genetic predisposition to AMD is dominated by polymorphisms in complement genes, it remains unclear how complement activation contributes to retinal atrophy. Here we demonstrate that complement is activated on photoreceptor outer segments (POS) in the retina peripheral to atrophic lesions associated with GA. When exposed to human serum following outer blood-retinal barrier breakdown, POS act as potent activators of the classical and alternative complement pathway. In mouse models of retinal degeneration, classical and alternative pathway complement activation on photoreceptors contributed to the loss of photoreceptor function. This was dependent on C5a-mediated recruitment of peripheral blood monocytes but independent of resident microglia. Genetic or pharmacologic inhibition of both classical and alternative complement C3 and C5 convertases was required to reduce progressive degeneration of photoreceptor rods and cones. Our study implicates systemic classical and alternative complement proteins and peripheral blood monocytes as critical effectors of localized retinal degeneration with potential relevance for the contribution of complement activation to GA.
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影响因子：
3.5
作者：
Kavanagh D;Yu Y;Schramm EC;Triebwasser M;Wagner EK;Raychaudhuri S;Daly MJ;Atkinson JP;Seddon JM
通讯作者：
Seddon JM
影响因子：
10.6
作者：
Gorin MB
通讯作者：
Gorin MB
DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
4.4
作者：
Hoffman, Joshua D.;Bailey, Jessica N. Cooke;Haines, Jonathan L.
通讯作者：
Haines, Jonathan L.
影响因子：
7.7
作者：
Eandi, Chiara M.;Messance, Hugo Charles;Sennlaub, Florian
通讯作者：
Sennlaub, Florian