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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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Staurosporine activates p38 MAPK and MK2, but does not induce CHOP in macrophages. Macrophages were left untreated (−), FC loaded for 6 h (+) using ac-LDL plus 58035, or treated for 6 h with 50 or 100 μM staurosporine. Immunoblot analysis was performed for phospho-p38 or phospho-MK2 (first and second panels), CHOP (third panel), and actin (bottom panel).
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fig2: Staurosporine activates p38 MAPK and MK2, but does not induce CHOP in macrophages. Macrophages were left untreated (−), FC loaded for 6 h (+) using ac-LDL plus 58035, or treated for 6 h with 50 or 100 μM staurosporine. Immunoblot analysis was performed for phospho-p38 or phospho-MK2 (first and second panels), CHOP (third panel), and actin (bottom panel).

Mentions: To determine whether an activator of the p38 pathway, other than FC loading would induce CHOP expression, we compared macrophages that were incubated under FC-loading conditions with those that were incubated with the known p38 activator, staurosporine (Yamaki et al., 2002). Treatment with 50 or 100 μM staurosporine for 6 h resulted in strong p38 activation, which was similar to that observed with 6 h of FC loading (Fig. 2, first panel). In addition, treatment with 100 μM staurosporine resulted in MK2 activation that was similar to that seen with FC loading (Fig. 2, second panel). However, neither concentration of staurosporine led to CHOP induction (Fig. 2, third panel). These data indicate that activation of the p38/MK2 pathway is not sufficient for CHOP induction.


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)

Staurosporine activates p38 MAPK and MK2, but does not induce CHOP in macrophages. Macrophages were left untreated (−), FC loaded for 6 h (+) using ac-LDL plus 58035, or treated for 6 h with 50 or 100 μM staurosporine. Immunoblot analysis was performed for phospho-p38 or phospho-MK2 (first and second panels), CHOP (third panel), and actin (bottom panel).
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Related In: Results  -  Collection

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

fig2: Staurosporine activates p38 MAPK and MK2, but does not induce CHOP in macrophages. Macrophages were left untreated (−), FC loaded for 6 h (+) using ac-LDL plus 58035, or treated for 6 h with 50 or 100 μM staurosporine. Immunoblot analysis was performed for phospho-p38 or phospho-MK2 (first and second panels), CHOP (third panel), and actin (bottom panel).
Mentions: To determine whether an activator of the p38 pathway, other than FC loading would induce CHOP expression, we compared macrophages that were incubated under FC-loading conditions with those that were incubated with the known p38 activator, staurosporine (Yamaki et al., 2002). Treatment with 50 or 100 μM staurosporine for 6 h resulted in strong p38 activation, which was similar to that observed with 6 h of FC loading (Fig. 2, first panel). In addition, treatment with 100 μM staurosporine resulted in MK2 activation that was similar to that seen with FC loading (Fig. 2, second panel). However, neither concentration of staurosporine led to CHOP induction (Fig. 2, third panel). These data indicate that activation of the p38/MK2 pathway is not sufficient for CHOP induction.

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