Free cholesterol-induced macrophage apoptosis is mediated by inositol-requiring enzyme 1 alpha-regulated activation of Jun N-terminal kinase.
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 (IRE1alpha) is an integral membrane protein of the ER that is a key signaling step in cholesterol-induced apoptosis in macrophages, activated by stress in the ER. However, the role of IRE1alpha 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 IRE1alpha. 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 IRE1alpha, or c-Jun NH2-terminal kinase.
Li
Fangming
F
Department of Neurology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430022, China.
Guo
Yi
Y
Sun
Shenggang
S
Jiang
Xin
X
Tang
Bingshan
B
Wang
Qizhang
Q
Wang
Ling
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D004722:Endoribonucleases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D002784:Cholesterol; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases