Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
Mol Ther. 2018 Jun 6;26(6):1568-1580. doi: 10.1016/j.ymthe.2018.03.012. Epub 2018 Mar 19.
Uveitis is an inflammatory disorder of the eye responsible for approximately 10%-15% of blindness in the US. In this study, we examined the role of the complement membrane attack complex (MAC) and the NLRP3 inflammasome in the pathogenesis of experimental autoimmune uveitis (EAU) in normal and C9 mice that are incapable of assembling the MAC. We discovered that the MAC and the NLRP3 inflammasome and associated production of IL-1β are elevated in EAU mice and that MAC may be involved in regulation of Th1 and Th17 cell differentiation. In contrast, MAC and the NLRP3 inflammasome were not elevated in C9 mice. However, EAU-associated pathophysiology including retinal structure and function were not rescued in C9 mice. Unexpectedly, AAV-mediated delivery of sCD59, an inhibitor of C9 incorporation into the MAC, successfully attenuated activation of the NLRP3 inflammasome and EAU pathology as well as MAC. Our studies provide an improved understanding of the role of the MAC and the NLRP3 inflammasome in EAU as well as suggest a novel approach for the treatment of uveitis.
葡萄膜炎是一种眼部炎症性疾病，约占美国失明病例的 10%-15%。在这项研究中，我们研究了补体膜攻击复合物（MAC）和 NLRP3 炎性体在正常和不能组装 MAC 的 C9 小鼠实验性自身免疫性葡萄膜炎（EAU）发病机制中的作用。我们发现，EAU 小鼠的 MAC 和 NLRP3 炎性体以及相关的 IL-1β产生升高，并且 MAC 可能参与调节 Th1 和 Th17 细胞分化。相比之下，C9 小鼠的 MAC 和 NLRP3 炎性体没有升高。然而，在 C9 小鼠中，与 EAU 相关的病理生理学，包括视网膜结构和功能，并没有得到挽救。出乎意料的是，AAV 介导的 sCD59（一种抑制 C9 掺入 MAC 的抑制剂）的传递成功地减弱了 NLRP3 炎性体和 EAU 病理以及 MAC 的激活。我们的研究提供了对 MAC 和 NLRP3 炎性体在 EAU 中的作用的更好理解，并为葡萄膜炎的治疗提供了一种新的方法。
