Interleukin-10 enhances the oxidized LDL-induced foam cell formation of macrophages by antiapoptotic mechanisms

Halvorsen, Bente; Wæhre, Torgun; Scholz, Hanne; Clausen, Ole Petter; Thüsen, Jan H. von der; Müller, Fredrik; Heimli, Hilde; Tonstad, Serena; Hall, Christian; Frøland, Stig S.; Biessen, Erik A.L.; Damås, Jan Kristian; Aukrust, Pål

doi:10.1194/jlr.m400324-jlr200

Cited by 80 publications

(59 citation statements)

References 37 publications

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“…IL-6 and IL-10 have also been previously shown to inhibit macrophage foam cell formation (27,28,30,31). IL-6 reduces AcLDL uptake by inhibiting SR gene expression (27), whereas IL-10 decreases foam cell formation by various mechanisms (28,30,31), some of which remain controversial (31). Our results demonstrate a clear cut mechanism by which IL-33 inhibits macrophage foam cell formation.…”

Section: Discussionmentioning

confidence: 45%

“…IL-33 decreases both AcLDL/OxLDL uptake and intracellular total and esterifed cholesterol levels but enhances cholesterol efflux through regulation of key genes involved in modified LDL uptake, cholesterol efflux/transport, and the storage of cholesteryl esters and triglycerides. IL-6 and IL-10 have also been previously shown to inhibit macrophage foam cell formation (27,28,30,31). IL-6 reduces AcLDL uptake by inhibiting SR gene expression (27), whereas IL-10 decreases foam cell formation by various mechanisms (28,30,31), some of which remain controversial (31).…”

Section: Discussionmentioning

confidence: 99%

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IL-33 Reduces Macrophage Foam Cell Formation

McLaren

Michael

Salter

et al. 2010

The Journal of Immunology

167

184

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Section: Discussionmentioning

confidence: 45%

Section: Discussionmentioning

confidence: 99%

IL-33 Reduces Macrophage Foam Cell Formation

McLaren

Michael

Salter

et al. 2010

The Journal of Immunology

167

184

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“…11,[13][14][15][16][17][18] Therefore, an important question that arises is how the many surviving macrophages in lesions avoid death induced by these and other factors. A plausible scenario is that macrophages also may encounter "survival factors" that, at least partially, counteract the death-promoting effects of OxLDL, FC loading, and other death inducers.…”

mentioning

confidence: 99%

Minimally Oxidized LDL Offsets the Apoptotic Effects of Extensively Oxidized LDL and Free Cholesterol in Macrophages

Boullier

Quehenberger

et al. 2006

ATVB

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Objective-Lipid-loaded macrophage-derived foam cells populate atherosclerotic lesions and produce many pro-inflammatory and plaque-destabilizing factors. An excessive accumulation of extensively oxidized low-density lipoprotein (OxLDL) or free cholesterol (FC), both of which are believed to be major lipid components of macrophages in advanced lesions, rapidly induces apoptosis in macrophages. Indeed, there is evidence of macrophage death in lesions, but how the surviving macrophages avoid death induced by OxLDL, FC, and other factors is not known. Methods and Results-Minimally oxidized LDL (mmLDL), which is an early product of progressive LDL oxidation in atherosclerotic lesions, countered OxLDL-induced or FC-induced apoptosis and stimulated macrophage survival both in cell culture and in vivo. DNA fragmentation and caspase-3 activity in OxLDL-treated peritoneal macrophages were significantly reduced by coincubation with mmLDL. In a separate set of experiments, mmLDL significantly reduced annexin V binding to macrophages in which apoptosis was induced by FC loading. In both cellular models, mmLDL activated a pro-survival PI3K/Akt signaling pathway, and PI3K inhibitors, wortmannin and LY294002, eliminated the pro-survival effect of mmLDL. Immunohistochemical examination demonstrated phospho-Akt in murine atherosclerotic lesions. Conclusions-Minimally

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“…Oxidized LDL (oxLDL) is not only a potent chemoattractant that recruits circulating monocytes to the intima and promotes their differentiation into macrophages but is also an inducer of macrophage apoptosis (47). When their apoptosis is inhibited by antiapoptotic proteins or inflammatory cytokines (18), macrophages survive, become activated, and avidly take up oxLDL through scavenger receptors (43). Progressive cytoplasmic accumulation of oxLDL by activated macrophages creates a characteristic "soap bubble" appearance, thereby giving them the name "foam cells."…”

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confidence: 99%

Fortilin reduces apoptosis in macrophages and promotes atherosclerosis

Pinkaew

Chen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilin-deficient ( fortilin+/−) mice and wild-type counterparts ( fortilin+/+) on a LDL receptor ( Ldlr)−/− apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 ( Apobec1)−/− hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin+/− mice exhibited significantly less atherosclerosis in their aortae than their fortilin +/+ littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin+/− mice contained fewer macrophages than those of fortilin+/+ mice. In addition, there were more apoptotic cells in the intima of fortilin+/− mice than in the intima of fortilin+/+ mice. Furthermore, peritoneal macrophages from fortilin+/− mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr−/− Apobec1−/− mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.

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Interleukin-10 enhances the oxidized LDL-induced foam cell formation of macrophages by antiapoptotic mechanisms

Cited by 80 publications

References 37 publications

IL-33 Reduces Macrophage Foam Cell Formation

IL-33 Reduces Macrophage Foam Cell Formation

Minimally Oxidized LDL Offsets the Apoptotic Effects of Extensively Oxidized LDL and Free Cholesterol in Macrophages

Fortilin reduces apoptosis in macrophages and promotes atherosclerosis

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