Inhibiting the NLRP3 inflammasome with MCC950 ameliorates retinal neovascularization and leakage by reversing the IL-1β/IL-18 activation pattern in an oxygen-induced ischemic retinopathy mouse model

被引:50
|
作者
Sui, Ailing [1 ]
Chen, Xiuping [2 ]
Shen, Jikui [3 ,4 ]
Demetriades, Anna M. [5 ]
Yao, Yiyun [1 ]
Yao, Yixuan [1 ]
Zhu, Yanji [1 ]
Shen, Xi [1 ]
Xie, Bing [1 ]
机构
[1] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Ophthalmol, Sch Med, Shanghai, Peoples R China
[2] Fudan Univ, Zhongshan Hosp, Dept Ophthalmol, Shanghai, Peoples R China
[3] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MA USA
[4] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MA USA
[5] New York Presbyterian Hosp, Dept Ophthalmol, Weill Cornell Med, New York, NY USA
关键词
OCULAR COMPLICATIONS; BETA; PDGF; THERAPY; VEGF; DEGENERATION; MACROPHAGES; MECHANISMS; DEFICIENT; PERICYTES;
D O I
10.1038/s41419-020-03076-7
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Activation of the nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3 (NLRP3) inflammasome plays an important role in ocular neovascularization. In our study, we found that the expression and activation levels of NLRP3 inflammasome components, including NLRP3, an apoptosis-associated speck-like protein (ASC) containing caspase activation and recruitment domain (CARD) and caspase-1 (CAS1), were significantly upregulated. In addition, we found interleukin (IL)-1 beta activity increased while IL-18 activity decreased in the retinas of oxygen-induced ischemic retinopathy (OIR) mice. MCC950, an inhibitor of NLRP3, reversed the IL-1 beta /IL-18 activation pattern, inhibited the formation of retinal neovascularization (RNV), decreased the number of acellular capillaries and reduced leakage of retinal vessels. Moreover, MCC950 could regulate the expression of endothelial cell- and pericyte function-associated molecules, such as vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1, VEGFR2, matrix metalloproteinase (MMP)2, MMP9, tissue inhibitor of metalloproteinases (TIMP)1, TIMP2, platelet-derived growth factor receptor-beta (PDGFR-beta), platelet-derived growth factor-B (PDGF-B), and angiopoietin2 (Ang2). In vitro, recombinant human (r)IL-18 and rIL-1 beta regulated the expression of endothelial cell- and pericyte function-associated molecules and the proliferation and migration of endothelial cells and pericytes. We therefore determined that inhibiting the NLRP3 inflammasome with MCC950 can regulate the function of endothelial cells and pericytes by reversing the IL-1 beta /IL-18 activation pattern to ameliorate RNV and leakage; thereby opening new avenues to treat RNV-associated ocular diseases.
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页数:16
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