Uric Acid Is a Danger Signal Activating NALP3 Inflammasome in Lung Injury Inflammation and Fibrosis
Uric Acid Is a Danger Signal Activating NALP3 Inflammasome in Lung Injury Inflammation and Fibrosis
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DOI：
10.1164/rccm.200808-1274oc
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发表时间：
2009-05-15
影响因子：
24.7
通讯作者：
Couillin, Isabelle
中科院分区：
文献类型：
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作者：
Gasse, Pamela;Riteau, Nicolas;Couillin, Isabelle
肺损伤通过髓样分化初级反应基因88（MyD 88）和IL-1受体1（IL-1 R1）信号通路导致肺部炎症和纤维化。肺损伤触发IL-10产生，炎症和纤维化的分子机制仍然知之甚少。Objective. Objective. To确定肺损伤是否依赖于NALP 3炎性体，如果博莱霉素（BLM）诱导的肺损伤触发尿酸的局部产生，从而激活NALP 3炎性体在lung.Methods：炎症后BLM管理在体内炎性体缺陷小鼠进行了评价。在接受尿酸合成抑制剂或降解尿酸的尿酸酶治疗的小鼠中，分析了肺部尿酸积累、炎症和纤维化。测量和主要结果：肺损伤取决于NALP 3炎性体，后者由BLM诱导的DNA损伤和降解后肺中局部产生的尿酸触发。使用尿酸合成抑制剂别嘌呤醇或尿酸酶降低尿酸水平导致BLM诱导的IL-1 β产生、肺部炎症、修复和纤维化减少。外源性尿酸晶体的局部给药重现了肺部炎症和修复，这依赖于NALP 3炎性体、MyD 88和IL-1 R1通路以及Toll样受体（TLR）2和TLR 4，但不依赖于IL-18受体。从受损细胞释放的尿酸构成了一种主要的内源性危险信号，它激活NALP 3炎性体，导致IL-1 β产生。降低尿酸组织水平代表了一种控制IL-1 β产生和慢性炎性肺病理学的新治疗方法。
Rationale Lung injury leads to pulmonary inflammation and fibrosis through myeloid differentiation primary response gene 88 (MyD88) and the IL-1 receptor 1 (IL-1R1) signaling pathway. The molecular mechanisms by which lung injury triggers IL-10 production, inflammation, and fibrosis remain poorly understood.Objectives: To determine if lung injury depends on the NALP3 inflammasome and if bleomycin (BLM)-induced lung injury triggers local production of uric acid, thereby activating the NALP3 inflammasome in the lung.Methods: Inflammation upon BLM administration was evaluated in vivo in inflammasome-deficient mice. Pulmonary uric acid accumulation, inflammation, and fibrosis were analyzed in mice treated with the inhibitor of uric acid synthesis or with uricase, which degrades uric acid.Measurements and Main Results: Lung injury depends on the NALP3 inflammasome, which is triggered by uric acid locally produced in the lung upon BLM-induced DNA damage and degradation. Reduction of uric acid levels using the inhibitor of uric acid synthesis allopurinol or uricase leads to a decrease in BLM-induced IL-1 beta production, lung inflammation, repair, and fibrosis. Local administration of exogenous uric acid crystals recapitulates lung inflammation and repair, which depend on the NALP3 inflammasome, MyD88, and IL-1R1 pathways and Toll-like receptor (TLR)2 and TLR4 for optimal inflammation but are independent of the IL-18 receptor.Conclusions: Uric acid released from injured cells constitutes a major endogenous danger signal that activates the NALP3 inflammasome, leading to IL-1 beta production. Reducing uric acid tissue levels represents a novel therapeutic approach to control IL-1 beta production and chronic inflammatory lung pathology.