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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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MKK3-dependent CHOP induction in macrophages is unique to FC loading. WT and Mkk3−/− macrophages were left untreated, FC loaded using ac-LDL plus 58035, or treated with 2.5 μg/ml tunicamycin or 2 μM thapsigargin for 7 h. Whole cell lysates were immunoblotted for phospho-p38 (top panel), total p38 (second panel), CHOP (third panel), and actin (bottom panel).
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fig3: MKK3-dependent CHOP induction in macrophages is unique to FC loading. WT and Mkk3−/− macrophages were left untreated, FC loaded using ac-LDL plus 58035, or treated with 2.5 μg/ml tunicamycin or 2 μM thapsigargin for 7 h. Whole cell lysates were immunoblotted for phospho-p38 (top panel), total p38 (second panel), CHOP (third panel), and actin (bottom panel).

Mentions: Other inducers of the UPR, such as the protein glycosylation inhibitor, tunicamycin, and the sarcoendoplasmic reticulum calcium ATPase inhibitor, thapsigargin, are known to activate p38 (Hung et al., 2004; Li and Holbrook, 2004). Therefore, we questioned whether p38 activation was necessary for CHOP induction by these two UPR inducers. As shown in Fig. 3 (top panel) p38 was phosphorylated after 5 h of treatment under FC-loading conditions or with tunicamycin or thapsigargin in WT macrophages. Phosphorylation of p38 under all three conditions was blocked completely in Mkk3−/− macrophages. Most importantly, only CHOP induction by FC loading was blocked by MKK3 deficiency (Fig. 3, third panel). Thus, the requirement for p38 activation in FC-induced CHOP expression is a unique feature of this particular inducer of the UPR.


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)

MKK3-dependent CHOP induction in macrophages is unique to FC loading. WT and Mkk3−/− macrophages were left untreated, FC loaded using ac-LDL plus 58035, or treated with 2.5 μg/ml tunicamycin or 2 μM thapsigargin for 7 h. Whole cell lysates were immunoblotted for phospho-p38 (top panel), total p38 (second panel), CHOP (third panel), and actin (bottom panel).
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Related In: Results  -  Collection

Show All Figures
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fig3: MKK3-dependent CHOP induction in macrophages is unique to FC loading. WT and Mkk3−/− macrophages were left untreated, FC loaded using ac-LDL plus 58035, or treated with 2.5 μg/ml tunicamycin or 2 μM thapsigargin for 7 h. Whole cell lysates were immunoblotted for phospho-p38 (top panel), total p38 (second panel), CHOP (third panel), and actin (bottom panel).
Mentions: Other inducers of the UPR, such as the protein glycosylation inhibitor, tunicamycin, and the sarcoendoplasmic reticulum calcium ATPase inhibitor, thapsigargin, are known to activate p38 (Hung et al., 2004; Li and Holbrook, 2004). Therefore, we questioned whether p38 activation was necessary for CHOP induction by these two UPR inducers. As shown in Fig. 3 (top panel) p38 was phosphorylated after 5 h of treatment under FC-loading conditions or with tunicamycin or thapsigargin in WT macrophages. Phosphorylation of p38 under all three conditions was blocked completely in Mkk3−/− macrophages. Most importantly, only CHOP induction by FC loading was blocked by MKK3 deficiency (Fig. 3, third panel). Thus, the requirement for p38 activation in FC-induced CHOP expression is a unique feature of this particular inducer of the UPR.

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