Oxidized Low-Density Lipoprotein Loading of Macrophages Downregulates TLR-Induced Proinflammatory Responses in a Gene-Specific and Temporal Manner through Transcriptional Control
Copyright © 2017 by The American Association of Immunologists, Inc..
Hypercholesterolemia is a key risk factor for atherosclerosis and leads to the uptake of native and oxidized low-density lipoprotein (oxLDL) by macrophages (Mϕs) and foam cell formation. Inflammatory processes accompany Mϕ foam cell formation in the artery wall, yet the relationship between Mϕ lipid loading and their response to inflammatory stimuli remains elusive. We investigated proinflammatory gene expression in thioglycollate-elicited peritoneal Mϕs, bone marrow-derived Mϕs and dendritic cells, and RAW264.7 cells. Loading with oxLDL did not induce peritoneal Mϕ apoptosis or modulate basal-level expression of proinflammatory genes. Upon stimulation of TLR4, the rapid induction of IFN-β was inhibited in cells loaded with oxLDL, whereas the induction of other proinflammatory genes by TLR4 (LPS), TLR3 (polyriboinosinic-polyribocytidylic acid), TLR2 (Pam3CSK4), and TLR9 (CpG) remained comparable within the first 2 h. Subsequently, the expression of a subset of proinflammatory genes (e.g., IL-1β, IL-6, CCL5) was reduced in oxLDL-loaded cells at the level of transcription. This phenomenon was partially dependent on NF erythroid 2-related factor 2 (NRF2) but not on nuclear liver X receptors α and β (LXRα,β), peroxisome proliferator-activated receptor-γ (PPARγ), and activating transcription factor 3 (ATF3). LPS-induced NF-κB reporter activity and intracellular signaling by NF-κB and MAPK pathways were comparable in oxLDL-loaded Mϕs, yet the binding of p65/RelA (the prototypic NF-κB family member) was reduced at IL-6 and CCL5 promoters. This study revealed that oxLDL loading of Mϕs negatively regulates transcription at late stages of TLR-induced proinflammatory gene expression and implicates epigenetic mechanisms such as histone deacetylase activity.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2017 |
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Erschienen: |
2017 |
Enthalten in: |
Zur Gesamtaufnahme - volume:199 |
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Enthalten in: |
Journal of immunology (Baltimore, Md. : 1950) - 199(2017), 6 vom: 15. Sept., Seite 2149-2157 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Jongstra-Bilen, Jenny [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 10.10.2017 Date Revised 29.01.2018 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.4049/jimmunol.1601363 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM274585693 |
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245 | 1 | 0 | |a Oxidized Low-Density Lipoprotein Loading of Macrophages Downregulates TLR-Induced Proinflammatory Responses in a Gene-Specific and Temporal Manner through Transcriptional Control |
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520 | |a Copyright © 2017 by The American Association of Immunologists, Inc. | ||
520 | |a Hypercholesterolemia is a key risk factor for atherosclerosis and leads to the uptake of native and oxidized low-density lipoprotein (oxLDL) by macrophages (Mϕs) and foam cell formation. Inflammatory processes accompany Mϕ foam cell formation in the artery wall, yet the relationship between Mϕ lipid loading and their response to inflammatory stimuli remains elusive. We investigated proinflammatory gene expression in thioglycollate-elicited peritoneal Mϕs, bone marrow-derived Mϕs and dendritic cells, and RAW264.7 cells. Loading with oxLDL did not induce peritoneal Mϕ apoptosis or modulate basal-level expression of proinflammatory genes. Upon stimulation of TLR4, the rapid induction of IFN-β was inhibited in cells loaded with oxLDL, whereas the induction of other proinflammatory genes by TLR4 (LPS), TLR3 (polyriboinosinic-polyribocytidylic acid), TLR2 (Pam3CSK4), and TLR9 (CpG) remained comparable within the first 2 h. Subsequently, the expression of a subset of proinflammatory genes (e.g., IL-1β, IL-6, CCL5) was reduced in oxLDL-loaded cells at the level of transcription. This phenomenon was partially dependent on NF erythroid 2-related factor 2 (NRF2) but not on nuclear liver X receptors α and β (LXRα,β), peroxisome proliferator-activated receptor-γ (PPARγ), and activating transcription factor 3 (ATF3). LPS-induced NF-κB reporter activity and intracellular signaling by NF-κB and MAPK pathways were comparable in oxLDL-loaded Mϕs, yet the binding of p65/RelA (the prototypic NF-κB family member) was reduced at IL-6 and CCL5 promoters. This study revealed that oxLDL loading of Mϕs negatively regulates transcription at late stages of TLR-induced proinflammatory gene expression and implicates epigenetic mechanisms such as histone deacetylase activity | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 7 | |a Cytokines |2 NLM | |
650 | 7 | |a Inflammation Mediators |2 NLM | |
650 | 7 | |a Lipoproteins, LDL |2 NLM | |
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700 | 1 | |a Zhang, Cindy X |e verfasserin |4 aut | |
700 | 1 | |a Wisnicki, Timothy |e verfasserin |4 aut | |
700 | 1 | |a Li, Mengyi K |e verfasserin |4 aut | |
700 | 1 | |a White-Alfred, Samantha |e verfasserin |4 aut | |
700 | 1 | |a Ilaalagan, Ragave |e verfasserin |4 aut | |
700 | 1 | |a Ferri, Dario M |e verfasserin |4 aut | |
700 | 1 | |a Deonarain, Ashley |e verfasserin |4 aut | |
700 | 1 | |a Wan, Mark H |e verfasserin |4 aut | |
700 | 1 | |a Hyduk, Sharon J |e verfasserin |4 aut | |
700 | 1 | |a Cummins, Carolyn L |e verfasserin |4 aut | |
700 | 1 | |a Cybulsky, Myron I |e verfasserin |4 aut | |
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