Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury

被引:152
作者
Sun, Rui [1 ,2 ]
Peng, Mengna [3 ]
Xu, Pengfei [4 ,5 ]
Huang, Feihong [6 ]
Xie, Yi [3 ]
Li, Juanji [3 ]
Hong, Ye [3 ]
Guo, Hongquan [6 ]
Liu, Qian [3 ]
Zhu, Wusheng [1 ,3 ,6 ]
机构
[1] Nanjing Med Univ, Jinling Clin Coll, Dept Neurol, 305 East Zhongshan Rd, Nanjing 210002, Jiangsu, Peoples R China
[2] Naval Med Univ, Mil Med Univ 2, Shanghai Changhai Hosp, Dept Neurol, Shanghai 200433, Peoples R China
[3] Nanjing Univ, Jinling Hosp, Med Sch, Dept Neurol, Nanjing 210002, Peoples R China
[4] Univ Sci & Technol China, Affiliated Hosp 1, Stroke Ctr, Div Life Sci & Med, Hefei 230036, Anhui, Peoples R China
[5] Univ Sci & Technol China, Affiliated Hosp 1, Dept Neurol, Div Life Sci & Med, Hefei 230036, Anhui, Peoples R China
[6] Southern Med Univ, Jinling Hosp, Sch Clin Med 1, Dept Neurol, Nanjing 210002, Peoples R China
关键词
Low-density lipoprotein receptor (LDLR); Inflammasome; Pyroptosis; Neuroinflammation; Ischemia; reperfusion; INFLAMMASOME ACTIVATION; THROMBOEMBOLIC STROKE; OXIDATIVE STRESS; ISCHEMIA; BRAIN; GSDMD; CHOLESTEROL; MECHANISMS; INHIBITION; PCSK9;
D O I
10.1186/s12974-020-01988-x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
BackgroundInflammatory response has been recognized as a pivotal pathophysiological process during cerebral ischemic stroke. NLRP3 inflammasome, involved in the regulation of inflammatory cascade, can simultaneously lead to GSDMD-executed pyroptosis in cerebral ischemia. Low-density lipoprotein receptor (LDLR), responsible for cholesterol uptake, was noted to exert potential anti-inflammatory bioactivities. Nevertheless, the role of LDLR in neuroinflammation mobilized by cerebral ischemia/reperfusion (I/R) has not been investigated.MethodsIschemic stroke mice model was accomplished by middle cerebral artery occlusion. Oxygen-glucose deprivation was employed after primary cortical neuron was extracted and cultured. A pharmacological inhibitor of NLRP3 (CY-09) was administered to suppress NLPR3 activation. Histological and biochemical analysis were performed to assess the neuronal death both in vitro and in vivo. In addition, neurological deficits and behavioral deterioration were evaluated in mice.ResultsThe expression of LDLR was downregulated following cerebral I/R injury. Genetic knockout of Ldlr enhanced caspase-1-dependent cleavage of GSDMD and resulted in severe neuronal pyroptosis. LDLR deficiency contributed to excessive NLRP3-mediated maturation and release of IL-1 beta and IL-18 under in vitro and in vivo ischemic conditions. These influences ultimately led to aggravated neurological deficits and long-term cognitive dysfunction. Blockade of NLRP3 substantially retarded neuronal pyroptosis in Ldlr(-/-) mice and cultured Ldlr(-/-) neuron after experimental stroke.ConclusionsThese results demonstrated that LDLR modulates NLRP3-mediated neuronal pyroptosis and neuroinflammation following ischemic stroke. Our findings characterize a novel role for LDLR as a potential therapeutic target in neuroinflammatory responses to acute cerebral ischemic injury.
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页数:17
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