Activation of NLRP3 inflammasome by cholesterol crystals in alcohol consumption induces atherosclerotic lesions.
Activation of NLRP3 inflammasome by cholesterol crystals in alcohol consumption induces atherosclerotic lesions.
复制标题
DOI：
10.1016/j.bbi.2017.02.014
复制
发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Haorah J
中科院分区：
文献类型：
--
作者：
Abdul-Muneer PM;Alikunju S;Mishra V;Schuetz H;Szlachetka AM;Burnham EL;Haorah J
流行病学研究表明，酗酒和中风的发病率之间有很强的联系，其潜在的致病机制仍有待了解。我们发现，在高脂饮食存在或不存在的情况下，慢性酒精（乙醇）消耗导致脑动脉/毛细血管损伤部位的免疫细胞浸润和胆固醇沉积诱导动脉粥样硬化。在酒精摄入中胆固醇转化为胆固醇晶体（CC）的尖锐边缘是激活NLRP 3炎性体、诱导脑动脉粥样硬化和动脉粥样硬化病变周围神经病变发展的关键。酒精的存在对于CC的形成和神经病理学的发展是至关重要的。因此，我们观察到酒精消耗升高了血浆胆固醇的水平、胆固醇的沉积和结晶以及NLRP 3炎性体的活化。这导致小动脉或毛细血管壁增厚，颅内血压升高。动脉粥样硬化病变周围明显的神经病变表明血管炎症是神经元变性的最初原因。我们使用NLRP 3基因沉默技术，在酒精/CC的剂量/时间依赖性效应的设置下，在人脑动脉/毛细血管内皮细胞的原代培养中，证明了NLRP 3激活和下游信号级联事件的分子机制。我们还在酒精使用者的血液样本中检测到CC，这验证了研究结果的临床重要性。最后，乙酰-L-肉碱和立普妥®联合治疗可预防胆固醇沉积、CC形成、NLRP 3激活、血管壁增厚和颅内血压升高。我们的结论是，酒精诱导的胆固醇积累和结晶激活了脑血管中的NLRP 3/caspase-1，导致动脉粥样硬化的早期发展。
Epidemiological studies showed a strong association between alcoholism and incidence of stroke, for which the underlying causative mechanisms remain to be understood. Here we found that infiltration of immune cellsanddeposition of cholesterol at the site of brain artery/capillary injury induced atherosclerosis in chronic alcohol (ethanol) consumption in the presence or absence of high-fat diet. Conversion of cholesterol into sharp edges of cholesterol crystals (CCs)in alcohol intake was key to activation of NLRP3 inflammasome, induction of cerebral atherosclerosis, and development of neuropathy around the atherosclerotic lesions. The presence of alcohol was critical for the formation of CCs and development of the neuropathology. Thus, we observed that alcohol consumption elevated the level of plasma cholesterol, deposition and crystallization of cholesterol, as well as activation of NLRP3 inflammasome. Thisled to arteriole or capillary walls thickening and increase intracranial blood pressure. Distinct neuropathy around the atherosclerotic lesions indicated vascular inflammation as an initial cause of neuronal degeneration. We demonstrated the molecular mechanisms of NLRP3 activation and downstream signaling cascade event in primary culture of human brain arterial/capillary endothelial cells in the setting of dose-/time-dependent effects of alcohol/CCs using NLRP3 gene silencing technique. We also detected CCs in blood samples from alcohol users, which validated the clinical importance of the findings. Finally,combined therapy of acetyl-L-carnitine and Lipitor® preventeddeposition of cholesterol, formation of CCs, activation of NLRP3, thickening of vessel walls, andelevation of intracranial blood pressure. We conclude thatalcohol-inducedaccumulation and crystallization of cholesterol activates NLRP3/caspase-1in the cerebralvessel that leads to early development of atherosclerosis.
登录
查看更多内容
β-环糊精联合的超帕磁铁氧化铁纳米颗粒的合成，用于选择性结合和检测胆固醇晶体。
DOI：
10.1039/c2cc17852d
发表时间：
2012-04-07
期刊：
Chemical communications (Cambridge, England)
影响因子：
--
作者：
Li H;El-Dakdouki MH;Zhu DC;Abela GS;Huang X
通讯作者：
Huang X
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
8.7
作者：
Galea, J;Armstrong, J;Holt, CM
通讯作者：
Holt, CM
影响因子：
4.4
作者：
Abela, George S.
通讯作者：
Abela, George S.
影响因子：
4.7
作者：
Haorah, James;Knipe, Bryan;Persidsky, Yuri
通讯作者：
Persidsky, Yuri