Differential modulation of retinal degeneration by Ccl2 and Cx3cr1 chemokine signalling.
Differential modulation of retinal degeneration by Ccl2 and Cx3cr1 chemokine signalling.
复制标题
DOI：
10.1371/journal.pone.0035551
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ali RR
中科院分区：
文献类型：
--
作者：
Luhmann UF;Lange CA;Robbie S;Munro PM;Cowing JA;Armer HE;Luong V;Carvalho LS;MacLaren RE;Fitzke FW;Bainbridge JW;Ali RR
小胶质细胞和巨噬细胞被募集到视网膜变性的部位，在那里局部细胞因子和趋化因子决定保护性或神经毒性小胶质细胞反应。确定Ccl 2-Ccr 2和Cx 3cl 1-Cx 3cr 1信号传导对视网膜病理学的作用是特别感兴趣的，因为其在年龄相关性黄斑变性（AMD）中的潜在作用。Ccl 2、Ccr 2和Cx 3cr 1信号传导缺陷损害巨噬细胞运输，但在几项相互矛盾的研究中，据报道显示出不同程度的年龄相关性视网膜变性。Ccl 2/Cx 3cr 1双敲除（CCDKO）小鼠显示出早发性视网膜变性，并已被建议作为AMD的模型。为了了解不同趋化因子敲除系的表型差异，并研究Ccl 2和/或Cx 3cr 1信号传导缺陷如何导致所述早发性视网膜变性，我们定义了CCDKO小鼠的原发性和继发性病理事件。为了控制遗传背景变异性，我们将原始表型与从CCDKO与C57 B1/6小鼠回交获得的单个Ccl 2、Cx 3cr 1和Ccl 2/Cx 3cr 1双敲除小鼠的表型进行了比较。我们发现，在CCDKO小鼠的主要病理事件的发展，在下外核层独立的光出生后第14天左右。RPE和血管病变随着年龄的增长而继发，并且在临床上与视网膜毛细血管扩张症相似，而不是脉络膜新生血管形成。此外，我们提供的证据表明，第三个常染色体隐性基因导致CCDKO小鼠和所有受影响的再衍生系的变性，随后证明了在Crb 1基因中自然发生的RD 8突变的共分离。通过比较CCDKO小鼠与再衍生的CCl 2 −/−/Crb 1 Rd 8/RD 8、Cx 3cr 1 −/−/Crb 1 Rd 8/RD 8和CCl 2 −/−/Cx 3cr 1 −/−/Crb 1 Rd 8/RD 8小鼠，我们观察到遗传背景和两种趋化因子信号通路对视网膜表型的差异调节。这些发现表明CCDKO小鼠不是AMD的模型，而是通过Ccl 2-Ccr 2和Cx 3cl 1-Cx 3cr 1趋化因子信号传导差异调节的遗传性视网膜变性的模型。
Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2−/−/Crb1Rd8/RD8, Cx3cr1−/−/Crb1Rd8/RD8 and CCl2−/−/Cx3cr1−/−/Crb1Rd8/RD8 mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings indicate that CCDKO mice are not a model of AMD, but a model for an inherited retinal degeneration that is differentially modulated by Ccl2-Ccr2 and Cx3cl1-Cx3cr1 chemokine signalling.
登录
查看更多内容
影响因子：
37.8
作者：
Combadière, C;Potteaux, S;Mallat, Z
通讯作者：
Mallat, Z
影响因子：
6
作者：
Joly, Sandrine;Francke, Mike;Reme, Charlotte E.
通讯作者：
Reme, Charlotte E.
影响因子：
15.9
作者：
Kreutzberg, GW
通讯作者：
Kreutzberg, GW
影响因子：
4.4
作者：
Hughes, EH;Schlichtenbrede, FC;Dick, AD
通讯作者：
Dick, AD
影响因子：
5.3
作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR