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

Recent evidence suggests that tumor necrosis factor ␣ (TNF␣) signaling in vascular cells can have antiatherogenic consequences, but the mechanisms are poorly understood. TNF␣ is released by free cholesterol-loaded apoptotic macrophages, and the clearance of these cells by phagocytic macrophages may help to limit plaque development. Macrophage cholesterol uptake induces ATP-binding cassette (ABC) transporter ABCA1 promoting cholesterol efflux to apolipoprotein A-I and reducing atherosclerosis. We show that TNF␣ induces ABCA1 mRNA and protein in control and cholesterolloaded macrophages and enhances cholesterol efflux to apolipoprotein A-I. The induction of ABCA1 by TNF␣ is reduced by 65% in I B kinase ␤-deficient macrophages and by 30% in p38␣-deficient macrophages, but not in jun kinase 1 (JNK1)-or JNK2-deficient macrophages. To evaluate the potential pathophysiological significance of these observations, we fed TNF␣-secreting free cholesterol-loaded apoptotic macrophages to a healthy macrophage monolayer (phagocytes). ABCA1 mRNA and protein were markedly induced in the phagocytes, a response that was mediated both by TNF␣ signaling and by liver X receptor activation. Thus, TNF␣ signals primarily through NF-B to induce ABCA1 expression in macrophages. In atherosclerotic plaques, this process may help phagocytic macrophages to efflux excess lipids derived from the ingestion of cholesterol-rich apoptotic corpses.atherosclerosis ͉ cytokine ͉ ATP-binding cassette transporter A BCA1 belongs to the ATP-binding cassette (ABC) transporter superfamily (1, 2) and promotes efflux of cholesterol and phospholipids from cellular membranes to apolipoprotein A-I (apoA-I) (3). In macrophages, oxysterol-activated liver X receptor (LXR) (4) and retinoid X receptor form a heterodimer that binds to a direct repeat 4 sequence (5, 6) located in the proximal promoter of the ABCA1 gene, resulting in increased gene transcription and increased cholesterol and phospholipid efflux to apoA-I (7). Bone marrow transplantation studies have shown that the expression of ABCA1 in macrophage foam cells has antiatherogenic consequences (8, 9).Atherosclerosis represents an inflammatory reaction in the arterial wall, initiated by the retention of lipoprotein lipids (10, 11). One of the most studied inflammatory cytokines is tumor necrosis factor ␣ (TNF␣), which is active in both human and rodent atherosclerotic plaques (10, 12). Many of the inflammatory properties of TNF␣ suggest that TNF␣ signaling is proatherogenic (13). Paradoxically, other studies have shown that signaling by means of the TNF␣ receptor I (p55) may have an overall atheroprotective effect (14) and moreover that TNF␣ signaling through NF-B in macrophages and vascular smooth muscle cells may be antiatherogenic (14-17). However, the mechanisms of atheroprotective effects of TNF␣ signaling in macrophages are not well understood. In this work, we show that TNF␣ induces ABCA1 through NF-B in macrophages and in phagocytes ingesting apoptotic cells, revealing a previously undescribed antiat...

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“…27. Macrophages deficient in p38␣ (p38␣ ⌬/⌬ ) were obtained from p38␣ f lox/f lox (p38␣ F/F ) mice crossed with LysMCre͞C57BL6J mice (53).…”

Section: Methodsmentioning

confidence: 99%

TNFα induces ABCA1 through NF-κB in macrophages and in phagocytes ingesting apoptotic cells

Gerbod-Giannone

Holleboom

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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101

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“…To determine whether TLR signaling in general was necessary for SRA-induced apoptosis in ER-stressed macrophages, we compared WT macrophages with those lacking the common TLR adaptor MyD88. We began with a simplified model of SRA-induced macrophage apoptosis (8), in which the SRA is engaged with the ligand fucoidan and the UPR is activated with the SERCA inhibitor thapsigargin. As shown in Fig.…”

Section: Tlr4 Is Required For Sra-induced Apoptosis In Er-stressed Mamentioning

confidence: 99%

“…Moreover, subpopulations of macrophages in apoptotic-rich areas of lesions are filled with lipoprotein-derived free cholesterol (FC) (15)(16)(17)(18)(19). In this scenario, the modified lipoproteins engage the SRA, and the lipoprotein-derived FC activates the UPR, leading to macrophage apoptosis (8). The UPR-SRA pathway of macrophage apoptosis requires activation of the protein kinase JNK (8), which also is known to be present in atheromata and promote atherogenesis (20).…”

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confidence: 99%

“…In this scenario, the modified lipoproteins engage the SRA, and the lipoprotein-derived FC activates the UPR, leading to macrophage apoptosis (8). The UPR-SRA pathway of macrophage apoptosis requires activation of the protein kinase JNK (8), which also is known to be present in atheromata and promote atherogenesis (20). Despite the new insight gained from these studies, the mechanisms by which SRA engagement contributes to apoptosis and how JNK activation is linked to the UPR or SRA were not elucidated.…”

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confidence: 99%

“…In this model, macrophage apoptosis is triggered by the endoplasmic reticulum (ER) stress pathway known as the unfolded protein response (UPR) in combination with engagement of the macrophage type A scavenger receptor (SRA), but not by either stimulus alone (8). The UPR is activated in advanced murine and human atherosclerotic lesions (9)(10)(11), and these lesions are known to contain a number of UPR activators (e.g., oxidant stress and nitric oxide) and SRA ligands (e.g., oxidized lipoproteins and advanced glycosylation end products) (12)(13)(14).…”

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confidence: 99%

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Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

Seimon

Obstfeld²,

Moore³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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166

194

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Macrophage pattern recognition receptors (PRRs) play key roles in innate immunity, but they also may contribute to disease processes under certain pathological conditions. We recently showed that engagement of the type A scavenger receptor (SRA), a PRR, triggers JNK-dependent apoptosis in endoplasmic reticulum (ER)-stressed macrophages. In advanced atherosclerotic lesions, the SRA, activated JNK, and ER stress are observed in macrophages, and macrophage death in advanced atheromata leads to plaque necrosis. Herein, we show that SRA ligands trigger apoptosis in ER-stressed macrophages by cooperating with another PRR, Tolllike receptor 4 (TLR4), to redirect TLR4 signaling from prosurvival to proapoptotic. Common SRA ligands activate both TLR4 signaling and engage the SRA. The TLR4 effect results in activation of the proapoptotic MyD88-JNK branch of TLR4, whereas the SRA effect silences the prosurvival IRF-3-IFN-␤ branch of TLR4. The normal cell-survival effect of LPS-induced TLR4 activation is converted into an apoptosis response by immunoneutralization of IFN-␤, and the apoptosis effect of SRA ligands is converted into a cell-survival response by reconstitution with IFN-␤. Thus, combinatorial signaling between two distinct PRRs results in a functional outcomemacrophage apoptosis that does not occur with either PRR alone. PRR-induced macrophage death may play important roles in advanced atherosclerosis and in other innate immunity-related processes in which the balance between macrophage survival and death is critical.apoptosis ͉ atherosclerosis ͉ scavenger receptor ͉ Toll-like receptor ͉ innate immunity

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The Impact of Insulin Resistance on Macrophage Death Pathways in Advanced Atherosclerosis

Tabas¹,

Seimon²,

Arellano³

et al. 2007

Novartis Foundation Symposia

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Macrophage death in advanced atherosclerosis causes plaque necrosis, which promotes plaque rupture and acute atherothrombotic vascular events. Of interest, plaque necrosis and atherothrombotic disease are markedly increased in diabetes and metabolic syndrome. We discovered a novel 'multi-hit' macrophage apoptosis pathway that appears to be highly relevant to advanced atherosclerosis. The elements of the pathway include: (a) activation of the unfolded protein response (UPR) by cholesterol overloading of the endoplasmic reticulum or by other UPR activators known to exist in atheromata; and (b) pro-apoptotic signalling involving the type A scavenger receptor (SRA). The downstream apoptosis effectors include CHOP (GADD153) for the UPR and JNK for SRA signalling. Remarkably, components of this pathway are enhanced in macrophages with defective insulin signalling, including UPR activation and SRA expression. As a result, insulin-resistant macrophages show increased susceptibility to apoptosis when exposed to UPR activators and SRA ligands. Moreover, the advanced lesions of atherosclerosis-prone mice reconstituted with insulin-resistant macrophages show increased macrophage apoptosis and plaque necrosis. Based on these findings, we propose that one mechanism of increased plaque necrosis and atherothrombotic vascular disease in insulin resistant syndromes is up-regulation of a two-hit signal transduction pathway involved in advanced lesional macrophage death.

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

Cited by 316 publications

References 79 publications

TNFα induces ABCA1 through NF-κB in macrophages and in phagocytes ingesting apoptotic cells

TNFα induces ABCA1 through NF-κB in macrophages and in phagocytes ingesting apoptotic cells

Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages

The Impact of Insulin Resistance on Macrophage Death Pathways in Advanced Atherosclerosis

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