Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation.
Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation.
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DOI：
10.1371/journal.pone.0011765
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发表时间：
2010-07-23
期刊：
影响因子：
3.7
通讯作者：
Eklund KK
中科院分区：
文献类型：
--
作者：
Rajamäki K;Lappalainen J;Oörni K;Välimäki E;Matikainen S;Kovanen PT;Eklund KK
动脉壁的慢性炎症是动脉粥样硬化发病机制中的关键因素，然而触发和维持炎症的因素仍然难以捉摸。炎性小体是细胞质半胱天冬酶-1激活蛋白复合物，其促进促炎细胞因子白细胞介素（IL）-1β和IL-18的成熟和分泌。最深入研究的炎性小体，NLRP 3炎性小体，被多种物质激活，包括晶体和颗粒物质。由于胆固醇晶体在动脉粥样硬化病变中含量丰富，并且IL-1β与动脉粥样硬化形成有关，因此我们探讨了胆固醇晶体通过激活炎性体途径促进炎症的可能性。在这里，我们表明，人类巨噬细胞贪婪地吞噬胆固醇晶体和胆固醇酯储存摄入的胆固醇。重要的是，胆固醇晶体诱导人单核细胞和巨噬细胞剂量依赖性分泌成熟IL-1β。胆固醇晶体诱导的IL-1β分泌是caspase-1依赖性的，表明涉及炎性体介导的途径。NLRP 3受体（NLRP 3炎性体中的关键组分）的沉默完全消除了晶体诱导的IL-1β分泌，从而将NLRP 3炎性体鉴定为巨噬细胞中的胆固醇晶体响应元件。晶体显示诱导溶酶体蛋白酶组织蛋白酶B渗漏到细胞质中，并且抑制该酶降低胆固醇晶体诱导的IL-1β分泌，表明NLRP 3炎性小体活化通过溶酶体去稳定化发生。胆固醇晶体诱导的巨噬细胞炎性小体活化可能是动脉粥样硬化病变中胆固醇代谢与炎症之间的重要联系。
Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1β and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1β has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway. Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1β from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1β was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1β secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1β secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization. The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions.
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影响因子：
8.7
作者：
Galea, J;Armstrong, J;Holt, CM
通讯作者：
Holt, CM
影响因子：
64.8
作者：
DOWER, SK;KRONHEIM, SR;URDAL, DL
通讯作者：
URDAL, DL
影响因子：
3.8
作者：
FLYNN, GL;SHAH, Y;HOFMANN, AF
通讯作者：
HOFMANN, AF
影响因子：
30.5
作者：
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影响因子：
5.4
作者：
BORASCHI, D;VILLA, L;TAGLIABUE, A
通讯作者：
TAGLIABUE, A