Wang Lei, Cano Marisol, Datta Sayantan, Wei Hong, Ebrahimi Katayoon B, Gorashi Yara, Garlanda Cecilia, Handa James T
Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, USA.
Istituto di Ricovero e Cura a Carattere Scientifico-Humanitas Clinical and Research Centre, Milan, Italy.
J Pathol. 2016 Dec;240(4):495-506. doi: 10.1002/path.4811.
The discovery that genetic abnormalities in complement factor H (FH) are associated with an increased risk for age-related macular degeneration (AMD), the most common cause of blindness among the elderly, raised hope of new treatments for this vision-threatening disease. Nonetheless, over a decade after the identification of this important association, how innate immunity contributes to AMD remains unresolved. Pentraxin 3 (PTX3), an essential component of the innate immunity system that plays a non-redundant role in controlling inflammation, regulates complement by interacting with complement components. Here, we show that PTX3 is induced by oxidative stress, a known cause of AMD, in the retinal pigmented epithelium (RPE). PTX3 deficiency in vitro and in vivo magnified complement activation induced by oxidative stress, leading to increased C3a, FB, and C3d, but not C5b-9 complex formation. Increased C3a levels, resulting from PTX3 deficiency, raised the levels of Il1b mRNA and secretion of activated interleukin (IL)-1β by interacting with C3aR. Importantly, PTX3 deficiency augmented NLRP3 inflammasome activation, resulting in enhanced IL-1β, but not IL-18, production by the RPE. Thus, in the presence of PTX3 deficiency, the complement and inflammasome pathways worked in concert to produce IL-1β in sufficient abundance to, importantly, result in macrophages accumulating in the choroid. These results demonstrate that PTX3 acts as an essential brake for complement and inflammasome activation by regulating the abundance of FH in the RPE, and provide critical insights into the complex interplay between oxidative stress and innate immunity in the early stages of AMD development. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
补体因子H（FH）的基因异常与年龄相关性黄斑变性（AMD）风险增加相关，而AMD是老年人失明的最常见原因，这一发现为治疗这种威胁视力的疾病带来了新希望。尽管如此，在确定这一重要关联十多年后，先天免疫如何导致AMD仍未得到解决。五聚素3（PTX3）是先天免疫系统的重要组成部分，在控制炎症中发挥非冗余作用，通过与补体成分相互作用来调节补体。在这里，我们表明PTX3由氧化应激诱导产生，氧化应激是AMD的已知病因，在视网膜色素上皮（RPE）中发挥作用。体外和体内PTX3缺乏会放大氧化应激诱导的补体激活，导致C3a、FB和C3d增加，但不会导致C5b - 9复合物形成。PTX3缺乏导致C3a水平升高，通过与C3aR相互作用提高了Il1b mRNA水平和活化白细胞介素（IL）-1β的分泌。重要的是，PTX3缺乏增强了NLRP3炎性小体的激活，导致RPE产生的IL - 1β增加，但IL - 18没有增加。因此，在PTX3缺乏的情况下，补体和炎性小体途径协同作用，产生足够量的IL - 1β，重要的是，导致巨噬细胞在脉络膜中积聚。这些结果表明，PTX3通过调节RPE中FH的丰度，作为补体和炎性小体激活的重要制动器，并为AMD发展早期氧化应激与先天免疫之间的复杂相互作用提供了关键见解。版权所有© 2016英国和爱尔兰病理学会。由约翰·威利父子有限公司出版。
