Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a MCP-1/CCL2 regulated phenomenon

Silva, Adriana Ribeiro; Pacheco, Patrícia; Vieira‐de‐Abreu, Adriana; Maya‐Monteiro, Clarissa M.; D'Alegria, Bárbara; Magalhães, Kelly Grace; Assis, Edson F. de; Bandeira‐Melo, Christianne; Castro‐Faria‐Neto, Hugo C.; Bozza, Patrı́cia T.

doi:10.1016/j.bbalip.2009.06.004

Cited by 64 publications

(70 citation statements)

References 62 publications

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“…12-HETE and 15-HETE, which are major metabolites of the 12/15-LOX pathway increased MCP-1 mRNA and protein expression in a mouse macrophage cell line [25]. On the other hand, recent evidence indicated that MCP-1 receptor CCR2 deficient mice have reduced ox-LDL induced lipid body assembly and LT release [26]. We therefore measured serum HETEs including 12-HETE, 15-HETE, and 5-HETE.…”

Section: Resultsmentioning

confidence: 99%

Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels

Imaizumi

Grijalva

Priceman

et al. 2010

Molecular Genetics and Metabolism

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Rationale We previously reported that mitogen-activated protein kinase phosphatase-1 (MKP-1) expression is necessary for oxidized phospholipids to induce monocyte chemoattractant protein-1 (MCP-1) secretion by human aortic endothelial cells. We also reported that inhibition of tyrosine phosphatases including MKP-1 ameliorated atherosclerotic lesions in mouse models of atherosclerosis. Objective This study was conducted to further investigate the specific role of MKP-1 in atherogenesis. Methods and Results We generated MKP-1−/−/apoE−/− double-knockout mice. At 24 weeks of age, the size, macrophage and dendritic cell content of atherosclerotic lesions of the aortic root were significantly lower (~-41% for lesions and macropahges, and ~-78% for dendritic cells) in MKP-1−/−/apoE−/− mice when compared with apoE−/− mice. Total cholesterol (−18.4%, p=0.045) and very low-density lipoprotein (VLDL)/ low-density lipoprotein (LDL) (-20.0%, p=0.052) cholesterol levels were decreased in MKP-1−/−/apoE−/− mice. Serum from MKP-1−/−/apoE−/− mice contained significantly lower levels of MCP-1 and possessed significantly reduced capability to induce monocyte migration in vitro. Moreover, peritoneal macrophages isolated from MKP-1−/−/apoE−/− mice produced significantly lower levels of MCP-1 when compared to peritoneal macrophages from apoE−/− mice. Furthermore, MKP-1−/−/apoE−/− mice had significantly reduced serum hydroxyeicosatetraenoic acids (HETEs) levels, which have been reported to induce MCP-1 levels. Conclusions Our results demonstrate that MKP-1 deficiency significantly decreases atherosclerotic lesion development in mice, in part, by affecting MCP-1 levels in the circulation and MCP-1 production by macrophages. MKP-1 may serve as a potential therapeutic target for the treatment of atherosclerotic disease.

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Section: Resultsmentioning

confidence: 99%

Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels

Imaizumi

Grijalva

Priceman

et al. 2010

Molecular Genetics and Metabolism

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“…Foamy macrophages are not only the product of an inflammatory response but amplify that response through the production of prostaglandin E2 and leukotrienes33, 45. ABCG1-deficient mice that have impaired cholesterol efflux show foamy macrophage formation and enhanced inflammation in the lung46.…”

Section: Characterization Of Foamy Macrophagesmentioning

confidence: 99%

Foamy macrophages and the progression of the human tuberculosis granuloma

et al. 2009

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The progression of tuberculosis from a latent, sub-clinical infection to active disease that culminates in transmission of infectious bacilli is determined locally at the level of the granuloma. This progression takes place even in the face of a robust immune response that, while it contains infection, is unable to eliminate the bacterium. The factors or environmental conditions that influence this progression remain to be determined. Recent advances have indicated that pathogen-induced dysregulation of host lipid synthesis and sequestration plays a critical role in this transition. The foamy macrophage appears to be a key player in both sustaining persistent bacteria and contributing to the tissue pathology that leads to cavitation and release of infectious bacilli.

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“…Initially considered as inert neutral lipidstorage compartments, LDs have become intensively studied organelles, implicated, for example, in the pathology of atherosclerosis, obesity, insulin resistance, type 2 diabetes [3], hepatic steatosis [4], cardiovascular disease, and inflammatory disorders [5,6]. The formation of LDs is a precisely regulated and inducible process which can be triggered by a variety of extracellular cues such as growth factors, long-chain fatty acids [7], oxidized low density lipoproteins [8] or by various environmental insults such as oxidative stress [9,10] and inflammatory stimuli [11]. LDs are rapidly induced under inflammatory conditions in leukocytes.…”

Section: Introductionmentioning

confidence: 99%

Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia

Khatchadourian

Bourque

Richard

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

108

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Lipid droplets (LDs) are neutral lipid-rich organelles involved in many cellular processes. A well-known example is their accumulation in leukocytes upon activation by pro-inflammatory stimuli such as lipopolysaccharides (LPS) derived from gram-negative bacteria. A role of LDs and LD-associated proteins during inflammation in the brain is unknown, however. We have now studied their dynamics and regulation in microglia, the resident immune cells in the brain. We find that LPS treatment of microglia leads to the accumulation in them of LDs, and enhancement of the size of LDs. This induction of LDs was abolished by triacsin C, an inhibitor of triglyceride biosynthesis. LPS strongly activated c-Jun N-terminal kinase (JNK) and p38 MAPK stress signaling pathways and increased the expression of LD-associated protein perilipin-2 (ADRP) in a time-dependent manner. Immunostaining showed that perilipin-2 in LPS-treated microglia predominantly colocalized with LDs. Inhibitors of p38 α/β (SB203580) and PI3K/Akt pathway (LY294002), but not that of JNK (SP600125), reduced LPS-induced LD accumulation and eliminated the activating effect of LPS on perilipin-2. In addition, cytosolic phospholipase A 2 (cPLA 2 -α), a key enzyme for arachidonic acid release, colocalized with LPS-induced LDs. These observations suggest that LDs may play an important role in eicosanoid synthesis in activated microglia; they provide a novel insight into the regulation of LDs in inflammatory cells of the brain and point to a potential role of p38 α/β in LPS-induced LD accumulation. Collectively, our findings imply that LD formation and perilipin-2 induction could be microglial biomarkers of inflammation in the central nervous system.

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Lipid bodies in oxidized LDL-induced foam cells are leukotriene-synthesizing organelles: a MCP-1/CCL2 regulated phenomenon

Cited by 64 publications

References 62 publications

Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels

Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels

Foamy macrophages and the progression of the human tuberculosis granuloma

Dynamics and regulation of lipid droplet formation in lipopolysaccharide (LPS)-stimulated microglia

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