Dataset Information

Palmitate and minimally-modified low-density lipoprotein cooperatively promote inflammatory responses in macrophages.

ABSTRACT: Increased consumption of Western-type diets and environmental insults lead to wide-spread increases in the plasma levels of saturated fatty acids and lipoprotein oxidation. The aim of this study is to examine whether palmitate and minimally modified low-density lipoprotein (mmLDL) exert an additive effect on macrophage activation. We found that CXCL2 and TNF-? secretion as well as ERK and p38 phosphorylation were additively increased by co-treatment of J774 macrophages with palmitate and mmLDL in the presence of lipopolysaccharide (LPS). Furthermore, the analysis of differentially expressed genes using the KEGG database revealed that several pathways, including cytokine-cytokine receptor interaction, and genes were significantly altered. These results were validated with real-time PCR, showing upregulation of Il-6, Csf3, Il-1?, and Clec4d. The present study demonstrated that palmitate and mmLDL additively potentiate the LPS-induced activation of macrophages. These results suggest the existence of synergistic mechanisms by which saturated fatty acids and oxidized lipoproteins activate immune cells.

SUBMITTER: Ann SJ

PROVIDER: S-EPMC5843266 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Palmitate and minimally-modified low-density lipoprotein cooperatively promote inflammatory responses in macrophages.

Ann Soo-Jin SJ Kim Ka-Kyung KK Cheon Eun Jeong EJ Noh Hye-Min HM Hwang Inhwa I Yu Je-Wook JW Park Sungha S Kang Seok-Min SM Manabe Ichiro I Miller Yury I YI Kim Sangwoo S Lee Sang-Hak SH

PloS one 20180308 3

Increased consumption of Western-type diets and environmental insults lead to wide-spread increases in the plasma levels of saturated fatty acids and lipoprotein oxidation. The aim of this study is to examine whether palmitate and minimally modified low-density lipoprotein (mmLDL) exert an additive effect on macrophage activation. We found that CXCL2 and TNF-α secretion as well as ERK and p38 phosphorylation were additively increased by co-treatment of J774 macrophages with palmitate and mmLDL i ...[more]

PMID: 29518116

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Project description:OBJECTIVE:HDL (high-density lipoprotein) infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. Studies have shown either anti- or proinflammatory effects of HDL in macrophages, and there is no consensus on the underlying mechanisms. Here, we interrogate the effects of HDL on inflammatory gene expression in macrophages. Approach and Results: We cultured bone marrow-derived macrophages, treated them with reconstituted HDL or HDL isolated from APOA1Tg;Ldlr-/- mice, and challenged them with lipopolysaccharide. Transcriptional profiling showed that HDL exerts a broad anti-inflammatory effect on lipopolysaccharide-induced genes and proinflammatory effect in a subset of genes enriched for chemokines. Cholesterol removal by POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine) liposomes or β-methylcyclodextrin mimicked both pro- and anti-inflammatory effects of HDL, whereas cholesterol loading by POPC/cholesterol-liposomes or acetylated LDL (low-density lipoprotein) before HDL attenuated these effects, indicating that these responses are mediated by cholesterol efflux. While early anti-inflammatory effects reflect reduced TLR (Toll-like receptor) 4 levels, late anti-inflammatory effects are due to reduced IFN (interferon) receptor signaling. Proinflammatory effects occur late and represent a modified endoplasmic reticulum stress response, mediated by IRE1a (inositol-requiring enzyme 1a)/ASK1 (apoptosis signal-regulating kinase 1)/p38 MAPK (p38 mitogen-activated protein kinase) signaling, that occurs under conditions of extreme cholesterol depletion. To investigate the effects of HDL on inflammatory gene expression in myeloid cells in atherosclerotic lesions, we injected reconstituted HDL into Apoe-/- or Ldlr-/- mice fed a Western-type diet. Reconstituted HDL infusions produced anti-inflammatory effects in lesion macrophages without any evidence of proinflammatory effects. CONCLUSIONS:Reconstituted HDL infusions in hypercholesterolemic atherosclerotic mice produced anti-inflammatory effects in lesion macrophages suggesting a beneficial therapeutic effect of HDL in vivo.

Dataset Information

Palmitate and minimally-modified low-density lipoprotein cooperatively promote inflammatory responses in macrophages.

Publications

Palmitate and minimally-modified low-density lipoprotein cooperatively promote inflammatory responses in macrophages.

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