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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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Induction of apoptosis by fucoidan plus CD-cholesterol/58035 in macrophages requires SRA expression. WT and Sra−/− macrophages were left untreated or were incubated with CD-cholesterol (CD-Chol)/58035 plus fucoidan (Fuc) for 18 h. The cells were stained with Alexa 488 Annexin V (green) and propidium iodide (red). Representative fluorescent images are shown. Quantitative apoptosis data for each condition are shown as described in the legend for Fig. 6. Data are expressed as mean ± SEM (n = 4). Bar, 25 μm.
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fig7: Induction of apoptosis by fucoidan plus CD-cholesterol/58035 in macrophages requires SRA expression. WT and Sra−/− macrophages were left untreated or were incubated with CD-cholesterol (CD-Chol)/58035 plus fucoidan (Fuc) for 18 h. The cells were stained with Alexa 488 Annexin V (green) and propidium iodide (red). Representative fluorescent images are shown. Quantitative apoptosis data for each condition are shown as described in the legend for Fig. 6. Data are expressed as mean ± SEM (n = 4). Bar, 25 μm.

Mentions: Neither fucoidan nor CML-BSA is specific for the SRA (Bucciarelli et al., 2002). Therefore, it was necessary to determine if the apoptosis-triggering effect of these molecules was dependent on the SRA. As shown in Fig. 7, CD-cholesterol/fucoidan–induced apoptosis was diminished markedly in Sra−/− macrophages. Apoptosis that was induced by β-VLDL plus fucoidan, or thapsigargin plus fucoidan, also was blocked in Sra−/− macrophages (unpublished data). Moreover, similar results were found using a blocking anti-SRA antibody with WT macrophages, which also was effective at blocking 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)–ac-LDL uptake (Fig. S5, A and B; available at http://www.jcb.org/cgi/content/full/jcb.200502078/DC1). Thus, fucoidan and CML-BSA induce apoptosis primarily through interaction with the SRA. We also found that FC loading by ac-LDL plus 58035 was blocked completely in Sra−/− macrophages, which confirmed that ac-LDL is taken up primarily through SRA (Fig. S5 C). Thus, the ability of ac-LDL (plus 58035) to induce apoptosis in macrophages can be explained by the ability of this lipoprotein to both activate the UPR (i.e., by way of FC loading of the cell) and engage the SRA.


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)

Induction of apoptosis by fucoidan plus CD-cholesterol/58035 in macrophages requires SRA expression. WT and Sra−/− macrophages were left untreated or were incubated with CD-cholesterol (CD-Chol)/58035 plus fucoidan (Fuc) for 18 h. The cells were stained with Alexa 488 Annexin V (green) and propidium iodide (red). Representative fluorescent images are shown. Quantitative apoptosis data for each condition are shown as described in the legend for Fig. 6. Data are expressed as mean ± SEM (n = 4). Bar, 25 μm.
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Related In: Results  -  Collection

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fig7: Induction of apoptosis by fucoidan plus CD-cholesterol/58035 in macrophages requires SRA expression. WT and Sra−/− macrophages were left untreated or were incubated with CD-cholesterol (CD-Chol)/58035 plus fucoidan (Fuc) for 18 h. The cells were stained with Alexa 488 Annexin V (green) and propidium iodide (red). Representative fluorescent images are shown. Quantitative apoptosis data for each condition are shown as described in the legend for Fig. 6. Data are expressed as mean ± SEM (n = 4). Bar, 25 μm.
Mentions: Neither fucoidan nor CML-BSA is specific for the SRA (Bucciarelli et al., 2002). Therefore, it was necessary to determine if the apoptosis-triggering effect of these molecules was dependent on the SRA. As shown in Fig. 7, CD-cholesterol/fucoidan–induced apoptosis was diminished markedly in Sra−/− macrophages. Apoptosis that was induced by β-VLDL plus fucoidan, or thapsigargin plus fucoidan, also was blocked in Sra−/− macrophages (unpublished data). Moreover, similar results were found using a blocking anti-SRA antibody with WT macrophages, which also was effective at blocking 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)–ac-LDL uptake (Fig. S5, A and B; available at http://www.jcb.org/cgi/content/full/jcb.200502078/DC1). Thus, fucoidan and CML-BSA induce apoptosis primarily through interaction with the SRA. We also found that FC loading by ac-LDL plus 58035 was blocked completely in Sra−/− macrophages, which confirmed that ac-LDL is taken up primarily through SRA (Fig. S5 C). Thus, the ability of ac-LDL (plus 58035) to induce apoptosis in macrophages can be explained by the ability of this lipoprotein to both activate the UPR (i.e., by way of FC loading of the cell) and engage the SRA.

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