Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo (USP), São Paulo, Brazil.
Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany.
Sci Rep. 2017 Jan 13;7:39884. doi: 10.1038/srep39884.
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.
尿酸是一种损伤相关分子模式（DAMP），从缺血组织和濒死细胞中释放出来，当结晶时，能够激活 NLRP3 炎性体。可溶性尿酸（sUA）在大型猿类的血清中浓度很高，在某些疾病出现晶体之前甚至更高。在本研究中，我们试图研究可溶性尿酸是否也可以激活 NLRP3 炎性体并诱导 IL-1β 的产生。我们监测了巨噬细胞在 sUA 刺激后的 ROS、线粒体面积和呼吸参数。我们观察到 sUA 在低氧环境中释放，并能够诱导 IL-1β 的释放。这一过程伴随着线粒体 ROS 的产生、ASC 斑点形成和 caspase-1 的激活。与 WT 和 Myd88 细胞相比，Nlrp3 巨噬细胞表现出受保护的氧化还原状态，最大和储备耗氧量比（OCR）增加，VDAC 蛋白水平升高。在一个以 sUA 水平升高为特征的疾病模型中，我们观察到 sUA、炎性体激活和纤维化之间存在相关性。这些发现表明 sUA 激活了 NLRP3 炎性体。我们提出，未来治疗肾纤维化的策略应包括阻断 sUA 或抑制其被吞噬细胞识别的策略。
