Oxidative stress and mitochondrial damage evoke complement component C5 activation independent of component C3 in dry age-related macular degeneration like NFE2L2/ PGC-1 -/- mouse model
Acta Ophthalmologica(2022)
摘要
Purpose Aging‐associated chronic oxidative stress and inflammation are known to be involved in various diseases, e.g. age‐related macular degeneration (AMD). Previously, we reported elevated oxidative stress, dysfunctional mitophagy and the accumulation of detrimental oxidized materials in the pigment epithelial (RPE) cells of dry AMD‐like nuclear factor erythroid 2‐related factor 2, and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha ( NFE2L2/PGC1α ) in a double knockout (dKO) mouse model. In this study, we show that mitochondrial‐derived oxidative stress leads to a buildup of complement component C5a, whereas the complement component C3a remains unaffected. Methods Immunohistochemical stained retina samples from one‐year‐old NRF2/PGC1α ‐/‐ and age‐matched wild‐type mice were used for confocal microscopy analysis. Results Immunohistochemical analysis of pathogen recognition receptors (PRRs) revealed an increase in levels of Toll‐like receptors 3 (TLR3) and 9 (TLR9), while those of NOD‐like receptor 3 (NLRP3) were decreased in NFE2L2/PGC1α ‐ /‐ retina. Further analysis showed a significant increase in complement component C5a independent of component C3, tightly regulated by complement factor H (CFH). Interestingly, we found that thrombin, a serine protease enzyme, was involved in enhancing the terminal pathway producing C5a, independent of C3. We also detect an increase in primary acute phase C‐reactive protein (CRP) and receptor for advanced glycation end products (RAGE) in NFE2L2/PGC1α ‐ /‐ retina. Conclusions Our study reveals previously unknown thrombin mediated C3 independent activation of C5a in the dry AMD like retina of NRF2/PGC1α double knockout mice model.
更多查看译文
关键词
oxidative stress,mitochondrial,complement
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要