Free cholesterol-induced macrophage apoptosis is mediated by inositol-requiring enzyme 1 alpha-regulated activation of Jun N-terminal kinase
Fangming Li
Department of Neurology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorCorresponding Author
Yi Guo
Department of Neurology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
*Corresponding author: Tel, 86-755-25533018; Fax, 86-755-25533497; E-mail, [email protected]Search for more papers by this authorShenggang Sun
Department of Neurology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China
Search for more papers by this authorXin Jiang
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorBingshan Tang
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorQizhang Wang
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorLing Wang
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorFangming Li
Department of Neurology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorCorresponding Author
Yi Guo
Department of Neurology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
*Corresponding author: Tel, 86-755-25533018; Fax, 86-755-25533497; E-mail, [email protected]Search for more papers by this authorShenggang Sun
Department of Neurology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China
Search for more papers by this authorXin Jiang
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorBingshan Tang
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorQizhang Wang
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorLing Wang
Department of Neurology, The Second Affiliated Hospital of Jinan University, Shenzhen 518020, China
Search for more papers by this authorThis work was supported by a grant from the Science Foundation of Guangdong Provincial Health Department (No. WSTJJ20041028)
Abstract
Macrophage death in advanced atherosclerotic lesions leads to lesional necrosis, possible plaque rupture, and acute vascular occlusion. A likely cause of macrophage death is the accumulation of free cholesterol (FC) leading to activation of endoplasmic reticulum (ER) stress-induced apoptosis. Inositol-requiring enzyme 1 alpha (IRE1α) is an integral membrane protein of the ERthat is a key signaling step in cholesterol-induced apoptosis in macrophages, activated by stress in the ER. However, the role of IRE1α in the regulation of ER stress-induced macrophage death and the mechanism for this process are largely unclear. In this study, a cell culture model was used to explore the mechanisms involved in the ER stress pathway of FC-induced macrophage death. The results herein showed that FC loading of macrophages leads to an apoptotic response that is partially dependent on initiation by activation of IRE1α. Taken together, these results showed that the IRE1-apoptosis-signaling kinase 1-c-Jun NH2-terminal kinase cascade pathway was required in this process. Moreover, the data suggested a novel cellular mechanism for cholesterol-induced macrophage death in advanced atherosclerotic lesions. The critical function of this signaling cascade is indicated by prevention of ER stress-induced apoptosis after inhibition of IRE1α, or c-Jun NH2-terminal kinase.
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