Uric acid promotes an acute inflammatory response to sterile cell death in mice
Uric acid promotes an acute inflammatory response to sterile cell death in mice
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DOI：
10.1172/jci40124
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发表时间：
2010-06-01
影响因子：
15.9
通讯作者：
Rock, Kenneth L.
中科院分区：
文献类型：
--
作者：
Kono, Hajime;Chen, Chun-Jen;Rock, Kenneth L.
坏死刺激炎症，这种反应在医学上是相关的，因为它有助于许多疾病的发病机制。人们认为坏死会刺激炎症，因为垂死的细胞会释放出被免疫系统识别的促炎分子。然而，对于这些分子的分子特性及其对体内反应的贡献知之甚少。在这里，我们研究了尿酸在小鼠对坏死细胞的炎症反应中的作用。我们发现，死亡细胞不仅在细胞内释放尿酸，而且在死后随着核酸的降解而大量产生尿酸。使用新开发的细胞内和/或细胞外尿酸水平降低的T-g小鼠，我们发现尿酸消耗大大减少了细胞死亡诱导的炎症反应。通过阻断尿酸的合成或在细胞外液中水解尿酸来降低尿酸水平的药物治疗也获得了类似的结果。重要的是，尿酸消耗选择性地抑制了对死亡细胞的炎症反应，而不是对微生物分子或无菌刺激颗粒的炎症反应。总的来说，我们的数据确定尿酸是一种从死亡细胞释放的促炎分子，在体内对细胞死亡诱导的炎症反应有重要贡献。
Necrosis stimulates inflammation, and this response is medically relevant because it contributes to the pathogenesis of a number of diseases. It is thought that necrosis stimulates inflammation because dying cells release proinflammatory molecules that are recognized by the immune system. However, relatively little is known about the molecular identity of these molecules and their contribution to responses in vivo. Here, we investigated the role of uric acid in the inflammatory response to necrotic cells in mice. We found that dead cells not only released intracellular stores of uric acid but also produced it in large amounts postmortem as nucleic acids were degraded. Using newly developed T-g mice that have reduced levels of uric acid either intracellularly and/or extracellularly, we found that uric acid depletion substantially reduces the cell death-induced inflammatory response. Similar results were obtained with pharmacological treatments that reduced uric acid levels either by blocking its synthesis or hydrolyzing it in the extracellular fluids. Importantly, uric acid depletion selectively inhibited the inflammatory response to dying cells but not to microbial molecules or sterile irritant particles. Collectively, our data identify uric acid as a proinflammatory molecule released from dying cells that contributes significantly to the cell death-induced inflammatory responses in vivo.