C3a triggers formation of sub-retinal pigment epithelium deposits via the ubiquitin proteasome pathway.
C3a triggers formation of sub-retinal pigment epithelium deposits via the ubiquitin proteasome pathway.
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DOI：
10.1038/s41598-018-28143-0
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发表时间：
2018-06-26
影响因子：
4.6
通讯作者：
Pierce EA
中科院分区：
文献类型：
--
作者：
Fernandez-Godino R;Pierce EA
在年龄相关性黄斑变性（AMD）的早期阶段中，连接补体系统激活和基底存款形成的机制尚未充分理解，这使得设计有效的治疗以防止疾病进展变得复杂。利用人胎儿视网膜色素上皮细胞（retinal pigment epithelial，RPE），建立了补体C3 a对RPE细胞的影响及其在亚RPE沉积形成中的作用的体外模型。这些研究的结果表明，C3活化后产生的C3 a足以通过补体驱动的蛋白酶体抑制诱导亚RPE沉积物的形成。C3 a结合C3 a受体（C3 aR），刺激RPE下方胶原IV和VI的沉积，并通过增加MMP-2活性来损害细胞外基质（ECM）周转，所有这些都是通过泛素蛋白酶体途径（UPP）的下调来介导的。通过添加C3 aR拮抗剂可以防止基底沉积物的形成，其恢复UPP活性和ECM周转。这些发现表明，基于细胞的模型可用于测试潜在的治疗药物在体外。这些数据表明，调节C3 aR介导的事件可能是治疗早期AMD的治疗方法。
The mechanisms that connect complement system activation and basal deposit formation in early stages of age-related macular degeneration (AMD) are insufficiently understood, which complicates the design of efficient therapies to prevent disease progression. Using human fetal (hf) retinal pigment epithelial (RPE) cells, we have established an in vitro model to investigate the effect of complement C3a on RPE cells and its role in the formation of sub-RPE deposits. The results of these studies revealed that C3a produced after C3 activation is sufficient to induce the formation of sub-RPE deposits via complement-driven proteasome inhibition. C3a binds the C3a receptor (C3aR), stimulates deposition of collagens IV and VI underneath the RPE, and impairs the extracellular matrix (ECM) turnover by increased MMP-2 activity, all mediated by downregulation of the ubiquitin proteasome pathway (UPP). The formation of basal deposits can be prevented by the addition of a C3aR antagonist, which restores the UPP activity and ECM turnover. These findings indicate that the cell-based model can be used to test potential therapeutic agents in vitro. The data suggest that modulation of C3aR-mediated events could be a therapeutic approach for treatment of early AMD.
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影响因子：
4.7
作者：
Ferrington DA;Hussong SA;Roehrich H;Kapphahn RJ;Kavanaugh SM;Heuss ND;Gregerson DS
通讯作者：
Gregerson DS
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：
16.6
作者：
de Bruin, Gerjan;Xin, Bo Tao;Overkleeft, Herman S.
通讯作者：
Overkleeft, Herman S.
影响因子：
14.8
作者：
Fernandez-Godino R;Garland DL;Pierce EA
通讯作者：
Pierce EA
DOI：
10.1073/pnas.222551899
发表时间：
2002-11-12
影响因子：
11.1
作者：
Crabb, JW;Miyagi, M;Hollyfield, JG
通讯作者：
Hollyfield, JG