Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor.
Macrophage death in advanced atherosclerosis promotes necrosis and plaque destabilization. A likely cause of macrophage death is accumulation of free cholesterol (FC) in the ER, leading to activation of the unfolded protein response (UPR) and C/EBP homologous protein (CHOP)-induced apoptosis. Here we show that p38 MAPK signaling is necessary for CHOP induction and apoptosis. Additionally, two other signaling pathways must cooperate with p38-CHOP to effect apoptosis. One involves the type A scavenger receptor (SRA). As evidence, FC loading by non-SRA mechanisms activates p38 and CHOP, but not apoptosis unless the SRA is engaged. The other pathway involves c-Jun NH2-terminal kinase (JNK)2, which is activated by cholesterol trafficking to the ER, but is independent of CHOP. Thus, FC-induced apoptosis requires cholesterol trafficking to the ER, which triggers p38-CHOP and JNK2, and engagement of the SRA. These findings have important implications for understanding how the UPR, MAPKs, and the SRA might conspire to cause macrophage death, lesional necrosis, and plaque destabilization in advanced atherosclerotic lesions.
Devries-Seimon
Tracie
T
Department of Medicine, Columbia University, New York, NY 10032, USA.
Li
Yankun
Y
Yao
Pin Mei
PM
Stone
Elizabeth
E
Wang
Yibin
Y
Davis
Roger J
RJ
Flavell
Richard
R
Tabas
Ira
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D050197:Atherosclerosis / Q000201:enzymology / Q000378:metabolism*; D002784:Cholesterol / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011487:Protein Conformation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D051117:Scavenger Receptors, Class A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D000099190:MAP-Kinase-Activated Kinase 2
D002784:Cholesterol; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051117:Scavenger Receptors, Class A; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C482531:Map2k3 protein, mouse