NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.
NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.
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动脉粥样硬化的炎症性质已得到充分证实，但引起动脉壁炎症的物质仍然很大程度上未知。无菌动物容易发生动脉粥样硬化，这表明内源性物质引发了炎症。成熟的动脉粥样硬化病变在坏死核心中含有肉眼可见的胆固醇晶体沉积物，但它们在动脉粥样硬化形成晚期的出现被认为使它们失去了作为原发炎症刺激物的资格。然而，使用一种新的显微技术，我们发现微小的胆固醇晶体存在于早期饮食引起的动脉粥样硬化病变中，并且它们在小鼠中的出现与炎症细胞的首次出现相一致。其他结晶物质可以通过刺激 caspase-1 激活 NLRP3（NALP3 或 Cryopyrin）炎症小体诱导炎症，从而导致白细胞介素 (IL)-1 家族细胞因子的裂解和分泌。在这里，我们发现胆固醇晶体在体外激活吞噬细胞中的 NLRP3 炎性体，该过程涉及吞噬溶酶体损伤。同样，腹膜内注射时，胆固醇晶体会诱发急性炎症，而缺乏 NLRP3 炎性体、组织蛋白酶 B、组织蛋白酶 L 或 IL-1 分子成分的小鼠，这种炎症会受到损害。此外，当低密度脂蛋白受体（LDLR）缺陷的小鼠被移植NLRP3缺陷、ASC（也称为PYCARD）缺陷或IL-1α/β缺陷的骨髓并喂食高胆固醇饮食时，它们的早期动脉粥样硬化和炎症小体依赖性IL-18水平显着降低。最低限度修饰的 LDL 可导致胆固醇结晶，同时巨噬细胞中 NLRP3 炎性体启动和激活。尽管氧化的 LDL 有可能在体内激活 NLRP3 炎症小体，但我们的结果表明，结晶胆固醇充当内源性危险信号，其在动脉或其他地方的沉积是炎症的早期原因，而不是晚期结果。这些发现为动脉粥样硬化的发病机制提供了新的见解，并指出了治疗该疾病的新的潜在分子靶点。
The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome,, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytesin vitroin a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1α/β-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasomein vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.
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影响因子：
82.9
作者：
Chen, Chun-Jen;Kono, Hajime;Rock, Kenneth L.
通讯作者：
Rock, Kenneth L.
影响因子：
15.9
作者：
Accad, M;Smith, SJ;Farese, RV
通讯作者：
Farese, RV
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1073/pnas.89.10.4471
发表时间：
1992-05-15
影响因子：
11.1
作者：
PIEDRAHITA, JA;ZHANG, SH;MAEDA, N
通讯作者：
MAEDA, N
影响因子：
56.9
作者：
Dostert, Catherine;Petrilli, Virginie;Tschopp, Jurg
通讯作者：
Tschopp, Jurg