Soluble Uric Acid Activates the NLRP3 Inflammasome.
Soluble Uric Acid Activates the NLRP3 Inflammasome.
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DOI：
10.1038/srep39884
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发表时间：
2017-01-13
影响因子：
4.6
通讯作者：
Camara NO
中科院分区：
文献类型：
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作者：
Braga TT;Forni MF;Correa-Costa M;Ramos RN;Barbuto JA;Branco P;Castoldi A;Hiyane MI;Davanso MR;Latz E;Franklin BS;Kowaltowski AJ;Camara NO
尿酸是一种损伤相关分子模式（DAMP），从缺血组织和垂死细胞释放，当结晶时，能够激活NLRP 3炎性体。可溶性尿酸（sUA）在大猩猩的血清中浓度很高，在晶体出现之前，在某些疾病中甚至更高。在本研究中，我们试图研究可溶性形式的尿酸是否也可以激活NLRP 3炎性小体并诱导IL-1β的产生。我们监测ROS，线粒体面积和呼吸参数的巨噬细胞后，UA刺激。我们观察到sUA在缺氧环境中释放，并且能够诱导IL-1β释放。该过程之后是线粒体ROS的产生、ASC斑点的形成和半胱天冬酶-1的活化。与WT和Myd 88 −/−细胞相比，Nlrp 3 −/−巨噬细胞呈现受保护的氧化还原状态，增加的最大和储备氧消耗率（OCR）和更高的VDAC蛋白水平。使用以sUA水平增加为特征的疾病模型，我们观察到sUA、炎性小体活化和纤维化之间的相关性。这些发现表明sUA激活NLRP 3炎性体。我们认为，未来肾纤维化的治疗策略应包括阻断sUA或抑制其被吞噬细胞识别的策略。
Uric acid is a damage-associated molecular pattern (DAMP), released from ischemic tissues and dying cells which, when crystalized, is able to activate the NLRP3 inflammasome. Soluble uric acid (sUA) is found in high concentrations in the serum of great apes, and even higher in some diseases, before the appearance of crystals. In the present study, we sought to investigate whether uric acid, in the soluble form, could also activate the NLRP3 inflammasome and induce the production of IL-1β. We monitored ROS, mitochondrial area and respiratory parameters from macrophages following sUA stimulus. We observed that sUA is released in a hypoxic environment and is able to induce IL-1β release. This process is followed by production of mitochondrial ROS, ASC speck formation and caspase-1 activation. Nlrp3−/− macrophages presented a protected redox state, increased maximum and reserve oxygen consumption ratio (OCR) and higher VDAC protein levels when compared to WT and Myd88−/− cells. Using a disease model characterized by increased sUA levels, we observed a correlation between sUA, inflammasome activation and fibrosis. These findings suggest sUA activates the NLRP3 inflammasome. We propose that future therapeutic strategies for renal fibrosis should include strategies that block sUA or inhibit its recognition by phagocytes.