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Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor.

Devries-Seimon T, Li Y, Yao PM, Stone E, Wang Y, Davis RJ, Flavell R, Tabas I - J. Cell Biol. (2005)

Bottom Line: Additionally, two other signaling pathways must cooperate with p38-CHOP to effect apoptosis.One involves the type A scavenger receptor (SRA).Thus, FC-induced apoptosis requires cholesterol trafficking to the ER, which triggers p38-CHOP and JNK2, and engagement of the SRA.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.

ABSTRACT
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.

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Model of how ER stress, MAPK pathways, and SRA engagement conspire to induce apoptosis in FC-loaded macrophages. Excess FC loading of the ER induces an ER stress response that leads to activation of p38 and JNK. Activation of p38, in turn, induces the UPR effector, CHOP. Three pathways—p38-CHOP, JNK, and engagement of the SRA—combine to induce apoptosis. Ac-LDL is able to trigger all three pathways, because it delivers cholesterol to the cells and is a ligand for the SRA.
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fig10: Model of how ER stress, MAPK pathways, and SRA engagement conspire to induce apoptosis in FC-loaded macrophages. Excess FC loading of the ER induces an ER stress response that leads to activation of p38 and JNK. Activation of p38, in turn, induces the UPR effector, CHOP. Three pathways—p38-CHOP, JNK, and engagement of the SRA—combine to induce apoptosis. Ac-LDL is able to trigger all three pathways, because it delivers cholesterol to the cells and is a ligand for the SRA.

Mentions: In summary, the results of this study support a model in which at least two other “hits” must conspire with the p38-UPR-CHOP pathway to effect apoptosis in macrophages: engagement of the SRA and activation of JNK2 (Fig. 10). These hits can be activated by separate inducers, as depicted in the figure, or by the same inducer, as is the case with ac-LDL.


Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor.

Devries-Seimon T, Li Y, Yao PM, Stone E, Wang Y, Davis RJ, Flavell R, Tabas I - J. Cell Biol. (2005)

Model of how ER stress, MAPK pathways, and SRA engagement conspire to induce apoptosis in FC-loaded macrophages. Excess FC loading of the ER induces an ER stress response that leads to activation of p38 and JNK. Activation of p38, in turn, induces the UPR effector, CHOP. Three pathways—p38-CHOP, JNK, and engagement of the SRA—combine to induce apoptosis. Ac-LDL is able to trigger all three pathways, because it delivers cholesterol to the cells and is a ligand for the SRA.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171235&req=5

fig10: Model of how ER stress, MAPK pathways, and SRA engagement conspire to induce apoptosis in FC-loaded macrophages. Excess FC loading of the ER induces an ER stress response that leads to activation of p38 and JNK. Activation of p38, in turn, induces the UPR effector, CHOP. Three pathways—p38-CHOP, JNK, and engagement of the SRA—combine to induce apoptosis. Ac-LDL is able to trigger all three pathways, because it delivers cholesterol to the cells and is a ligand for the SRA.
Mentions: In summary, the results of this study support a model in which at least two other “hits” must conspire with the p38-UPR-CHOP pathway to effect apoptosis in macrophages: engagement of the SRA and activation of JNK2 (Fig. 10). These hits can be activated by separate inducers, as depicted in the figure, or by the same inducer, as is the case with ac-LDL.

Bottom Line: Additionally, two other signaling pathways must cooperate with p38-CHOP to effect apoptosis.One involves the type A scavenger receptor (SRA).Thus, FC-induced apoptosis requires cholesterol trafficking to the ER, which triggers p38-CHOP and JNK2, and engagement of the SRA.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Columbia University, New York, NY 10032, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus