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.
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.
复制标题
抑制 NLRP3 炎性体与 MCC950 通过逆转氧诱导缺血性视网膜病变小鼠模型中的 IL-1β/IL-18 激活模式改善视网膜新生血管和渗漏。
DOI：
10.1038/s41419-020-03076-7
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发表时间：
2020-10-22
影响因子：
9
通讯作者：
Xie B
中科院分区：
文献类型：
--
作者：
Sui A;Chen X;Shen J;Demetriades AM;Yao Y;Yao Y;Zhu Y;Shen X;Xie B
核巧酸结合域富含亮氨酸重复序列和含化yrin结构域的受体3（NLRP 3）炎性体的激活在眼部新生血管形成中起重要作用。在我们的研究中，我们发现NLRP 3炎性体组分的表达和活化水平，包括NLRP 3，一种包含半胱天冬酶活化和募集结构域（CARD）和半胱天冬酶-1（CAS 1）的骨化相关斑点样蛋白（ASC），显著上调。此外，我们发现在氧诱导的缺血性视网膜病变（OIR）小鼠的视网膜中，白细胞介素（IL）-1β活性增加，而IL-18活性降低。NLRP 3抑制剂MCC 950可逆转IL-1β/IL-18激活模式，抑制视网膜新生血管（RNV）形成，减少脱细胞毛细血管数量，减少视网膜血管渗漏。此外，MCC 950可调节内皮细胞和周细胞功能相关分子的表达，如血管内皮生长因子（VEGF）、VEGF受体（VEGFR）1、VEGFR 2、基质金属蛋白酶（MMP）2、MMP 9、金属蛋白酶组织抑制剂（TIMP）1、TIMP 2、血小板衍生生长因子受体-β（PDGFR-β）、血小板衍生生长因子-B（PDGF-B）、和血管生成素2（Ang 2）。在体外，重组人（r）IL-18和rIL-1β调节内皮细胞和周细胞功能相关分子的表达以及内皮细胞和周细胞的增殖和迁移。因此，我们确定用MCC 950抑制NLRP 3炎性体可以通过逆转IL-1β/IL-18活化模式来调节内皮细胞和周细胞的功能，以改善RNV和渗漏;从而开辟治疗RNV相关眼病的新途径。
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)-1β 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-1β/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-β (PDGFR-β), platelet-derived growth factor-B (PDGF-B), and angiopoietin2 (Ang2). In vitro, recombinant human (r)IL-18 and rIL-1β 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-1β/IL-18 activation pattern to ameliorate RNV and leakage; thereby opening new avenues to treat RNV-associated ocular diseases.
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影响因子：
3.3
作者：
Ferrara N
通讯作者：
Ferrara N
缺乏周细胞会导致内皮增生和异常血管形态发生。
影响因子：
7.8
作者：
Hellstrom, M;Gerhardt, H;Kalen, M;Li, X;Eriksson, U;Wolburg, H;Betsholtz, C
通讯作者：
Betsholtz, C
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.6
作者：
Kajal, Kirti;Panda, Abir K.;Sa, Gaurisankar
通讯作者：
Sa, Gaurisankar
DOI：
10.1016/j.bbrc.2008.12.161
发表时间：
2009-02-20
影响因子：
3.1
作者：
Herzog, Christian;Haun, Randy S.;Kaushal, Varsha;Mayeux, Philip R.;Shah, Sudhir V.;Kaushal, Gur P.
通讯作者：
Kaushal, Gur P.