NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration.
NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration.
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DOI：
10.3390/ijms17010073
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发表时间：
2016-01-08
影响因子：
5.6
通讯作者：
Chan CC
中科院分区：
文献类型：
--
作者：
Wang Y;Hanus JW;Abu-Asab MS;Shen D;Ogilvy A;Ou J;Chu XK;Shi G;Li W;Wang S;Chan CC
炎症和氧化应激参与了老年性黄斑变性(AMD)，可能与主要组织相容性复合体(MHC)/异核体不相容/端粒酶相关蛋白1、富亮氨酸重复序列或核苷酸结合结构域、富含亮氨酸重复序列家族和含比林结构域3(NLRP3)炎症体的神经元凋亡抑制蛋白/II类转录激活有关。在本研究中，我们使用了一种翻译方法来解决这一假设。在老年性黄斑变性患者的视网膜色素上皮和光感受器病变中，我们观察到NLRP3、白介素1β原(IL-1β)和白介素18原基因的表达水平升高。在体外，氧化应激或脂多糖(LPS)刺激成人视网膜色素上皮(ARPE-19)细胞株也能引起类似的增加，而siRNA转染的细胞则抑制了NLRP3的表达。ARPE-19细胞超微结构研究显示细胞质肿胀，线粒体损伤，并出现自噬体样结构。NLRP3阳性斑点位于自噬体样结构内或细胞外间隙。接下来，我们使用了AMD小鼠模型，CCL2/CX3CR1在RD8背景(DKO RD8)上进行了双基因敲除，以确定其在体内的相关性。对这些小鼠RPE的超微结构研究显示，线粒体、自噬体样结构和细胞质空泡受损，这让人想起应激状态下ARPE-19细胞的病理。提示NLRP3炎症体可能参与了AMD的发病过程。
Inflammation and oxidative stress are involved in age-related macular degeneration (AMD) and possibly associated with an activation of neuronal apoptosis inhibitor protein/class II transcription activator of the Major Histocompatibility Complex (MHC)/heterokaryon incompatibility/telomerase-associated protein 1, leucine-rich repeat or nucleotide-binding domain, leucine-rich repeat-containing family, and pyrin domain-containing 3 (NLRP3) inflammasome. In the present study, we used a translational approach to address this hypothesis. In patients with AMD, we observed increased mRNA levels of NLRP3, pro-interleukin-1 beta (IL-1β) and pro-IL-18 in AMD lesions of the retinal pigment epithelium (RPE) and photoreceptor. In vitro, a similar increase was evoked by oxidative stress or lipopolysaccharide (LPS) stimulation in the adult retinal pigment epithelium (ARPE-19) cell line, and the increase was reduced in siRNA transfected cells to knockdown NLRP3. Ultrastructural studies of ARPE-19 cells showed a swelling of the cytoplasm, mitochondrial damage, and occurrence of autophagosome-like structures. NLRP3 positive dots were detected within autophagosome-like structures or in the extracellular space. Next, we used a mouse model of AMD, Ccl2/Cx3cr1 double knockout on rd8 background (DKO rd8) to ascertain the in vivo relevance. Ultrastructural studies of the RPE of these mice showed damaged mitochondria, autophagosome-like structures, and cytoplasmic vacuoles, which are reminiscent of the pathology seen in stressed ARPE-19 cells. The data suggest that the NLRP3 inflammasome may contribute in AMD pathogenesis.