The deposition of cholesterol-rich lipoproteins in the arterial wall triggers macrophage inflammatory responses, which promote atherosclerosis. The NLRP3 inflammasome aggravates atherosclerosis; however, cellular mechanisms connecting macrophage cholesterol accumulation to inflammasome activation are poorly understood. We investigated the mechanisms of NLRP3 inflammasome activation in cholesterol-loaded macrophages and in atherosclerosis-prone mice with defects in macrophage cholesterol efflux. We found that accumulation of cholesterol in macrophages treated with modified LDL or cholesterol crystals, or in macrophages defective in the cholesterol efflux promoting transporters ABCA1 and ABCG1, leads to activation of NLRP3 inflammasomes as a result of increased cholesterol trafficking from the plasma membrane to the ER, via Aster-B. In turn, the accumulation of cholesterol in the ER activates the inositol triphosphate-3 receptor, CaMKII/JNK, and induces NLRP3 deubiquitylation by BRCC3. An NLRP3 deubiquitylation inhibitor or deficiency of , an essential scaffolding protein in the BRCC3-containing cytosolic complex, suppressed inflammasome activation, neutrophil extracellular trap formation (NETosis), and atherosclerosis in vivo. These results identify a link between the trafficking of cholesterol to the ER, NLRP3 deubiquitylation, inflammasome activation, and atherosclerosis.

中文翻译：

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胆固醇转运至内质网导致 CaMKII/JNK/NLRP3 激活并促进动脉粥样硬化

富含胆固醇的脂蛋白在动脉壁沉积会引发巨噬细胞炎症反应，从而促进动脉粥样硬化。 NLRP3炎症小体加重动脉粥样硬化；然而，人们对巨噬细胞胆固醇积累与炎症小体激活之间的细胞机制知之甚少。我们研究了负载胆固醇的巨噬细胞和巨噬细胞胆固醇流出缺陷的易发生动脉粥样硬化的小鼠中 NLRP3 炎症小体激活的机制。我们发现，经过修饰的 LDL 或胆固醇晶体处理的巨噬细胞中，或者在胆固醇流出促进转运蛋白 ABCA1 和 ABCG1 有缺陷的巨噬细胞中，胆固醇的积累会导致 NLRP3 炎症小体的激活，因为胆固醇从质膜到内质网的运输增加。 ，通过 Aster-B。反过来，内质网中胆固醇的积累会激活肌醇三磷酸-3 受体 CaMKII/JNK，并诱导 BRCC3 使 NLRP3 去泛素化。 NLRP3 去泛素化抑制剂或 NLRP3 的缺乏（含 BRCC3 的胞质复合物中的一种重要支架蛋白）可抑制体内炎症小体激活、中性粒细胞胞外陷阱形成 (NETosis) 和动脉粥样硬化。这些结果确定了胆固醇运输至内质网、NLRP3 去泛素化、炎症小体激活和动脉粥样硬化之间的联系。