Department Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland.
The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
Cell Rep. 2020 Feb 18;30(7):2209-2224.e5. doi: 10.1016/j.celrep.2020.01.064.
Retinal degeneration is a form of neurodegenerative disease and is the leading cause of vision loss globally. The Toll-like receptors (TLRs) are primary components of the innate immune system involved in signal transduction. Here we show that TLR2 induces complement factors C3 and CFB, the common and rate-limiting factors of the alternative pathway in both retinal pigment epithelial (RPE) cells and mononuclear phagocytes. Neutralization of TLR2 reduces opsonizing fragments of C3 in the outer retina and protects photoreceptor neurons from oxidative stress-induced degeneration. TLR2 deficiency also preserves tight junction expression and promotes RPE resistance to fragmentation. Finally, oxidative stress-induced formation of the terminal complement membrane attack complex and Iba1+ cell infiltration are strikingly inhibited in the TLR2-deficient retina. Our data directly implicate TLR2 as a mediator of retinal degeneration in response to oxidative stress and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology.
视网膜变性是一种神经退行性疾病，是全球范围内导致视力丧失的主要原因。Toll 样受体（TLR）是先天免疫系统的主要组成部分，参与信号转导。在这里，我们表明 TLR2 诱导补体因子 C3 和 CFB，它们是视网膜色素上皮（RPE）细胞和单核吞噬细胞中替代途径的共同和限速因子。TLR2 的中和减少了外视网膜中 C3 的调理片段，并保护光感受器神经元免受氧化应激诱导的变性。TLR2 缺乏还保持了紧密连接的表达，并促进 RPE 抵抗碎片化。最后，氧化应激诱导的末端补体膜攻击复合物的形成和 Iba1+细胞浸润在 TLR2 缺陷的视网膜中明显受到抑制。我们的数据直接表明 TLR2 是氧化应激反应中视网膜变性的介质，并将 TLR2 作为氧化损伤与补体介导的视网膜病理学之间的桥梁。
