Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA188404 | ENA |
REPOSITORIES: ENA
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Project description:Elevated plasma levels of High Density Lipoprotein (HDL) are associated with decreased risk of cardiovascular disease (CVD). The protective role of HDL in atherosclerosis has been attributed primarily to its ability to remove excess cholesterol from lipid-laden macrophages (foam cells) within the arterial walls. However, clinical trials that raise HDL cholesterol levels have failed to show a benefit casting doubts on our basic understanding of HDL function. Atherosclerosis is a chronic inflammatory condition underlying CVD and driven in part by the recognition of metabolic danger signals by innate immune receptors on macrophages. A potential feature that could contribute to HDL’s protective effects in CVD could be HDL's anti-inflammatory nature, such as its ability to reduce endothelial cell activation. However, the molecular mechanisms by which HDL reduces inflammatory macrophage responses remain poorly understood and difficult to separate from its cholesterol depleting activity. Here we show that HDL protects against Toll like receptor (TLR)-induced inflammation both in vivo and in vitro under normocholesteremic conditions by suppressing the transcription of inflammatory cytokines in a manner independent of its ability to remove cellular cholesterol. We identify Activating Transcription Factor 3 (ATF3), a transcriptional repressor of the CREB family of basic leucine zipper transcription factors, as a HDL-inducible regulator of macrophage activation. HDL’s ability to down modulate TLR responses was severely compromised in ATF3-deficient cells demonstrating that ATF3 mediates HDL's anti-inflammatory effects and may explain the broad anti-inflammatory functions of HDL.
2013-12-08 | GSE44034 | GEO
Project description:Elevated plasma levels of High Density Lipoprotein (HDL) are associated with decreased risk of cardiovascular disease (CVD). The protective role of HDL in atherosclerosis has been attributed primarily to its ability to remove excess cholesterol from lipid-laden macrophages (foam cells) within the arterial walls. However, clinical trials that raise HDL cholesterol levels have failed to show a benefit casting doubts on our basic understanding of HDL function. Atherosclerosis is a chronic inflammatory condition underlying CVD and driven in part by the recognition of metabolic danger signals by innate immune receptors on macrophages. A potential feature that could contribute to HDL’s protective effects in CVD could be HDL's anti-inflammatory nature, such as its ability to reduce endothelial cell activation. However, the molecular mechanisms by which HDL reduces inflammatory macrophage responses remain poorly understood and difficult to separate from its cholesterol depleting activity. Here we show that HDL protects against Toll like receptor (TLR)-induced inflammation both in vivo and in vitro under normocholesteremic conditions by suppressing the transcription of inflammatory cytokines in a manner independent of its ability to remove cellular cholesterol. We identify Activating Transcription Factor 3 (ATF3), a transcriptional repressor of the CREB family of basic leucine zipper transcription factors, as a HDL-inducible regulator of macrophage activation. HDL’s ability to down modulate TLR responses was severely compromised in ATF3-deficient cells demonstrating that ATF3 mediates HDL's anti-inflammatory effects and may explain the broad anti-inflammatory functions of HDL. Bone marrow-derived macrophages (BMDMs) were obtained by culturing bone marrow cells from 6 to 8 week old wildtype C57BL/6 mice in DMEM supplemented with 10% FCS, 10 mg ml-1 Ciprobay-500 and 40 ng ml-1 M-CSF (R & D Systems). BMDMs of wt mice were pretreated for 6 h with HDL (2 mg ml-1 ) then stimulated with CpG (100 nM) for 4 h. Further wild type or Atf3-deficient BMDMs were pretreated with 2 mg ml-1 HDL for 6 h and subsequently stimulated with CpG (100 nM) or P3C (50 ng ml-1) for 4 h. For carotid artery injury approximately 12-week old male WT and Atf3-deficient mice were anesthetized with i.p. injection of 150 mg/kg ketaminehydrochloride (Ketanest, Pharmacia) and 0.1 mg/kg xylazinehydrochloride (Rompun 2%, Bayer). A small incision from the cranial apex of the sternum to just below the mandible was made. After careful preparation of an approximately 6 mm long segment proximal of the bifurcation, the common carotid artery was electrically denuded. A 4 mm long lesion was made by applying two serial 5 second bursts of 2 Watt using 2 mm wide forceps. The skin was then sutured and the mice allowed to recover in individual cages before returning to their littermates. Three hours later the mice received a single 200 ?l i.v. injection of 20 mg/kg HDL or PBS.
2013-12-08 | E-GEOD-44034 | biostudies-arrayexpress
Project description:HDL infusion reduces atherosclerosis in animal models and is being evaluated as a treatment in humans. While some studies have shown anti-inflammatory effects of HDL in macrophages, others have reported pro-inflammatory effects and there is no consensus on underlying mechanisms. Transcriptional profiling reveals that HDL-mediated cholesterol efflux leads to both pro- and anti-inflammatory effects in LPS-stimulated macrophages. While early anti-inflammatory effects reflect reduced TLR4 levels, late anti-inflammatory effects are due to reduced interferon receptor signaling. Pro-inflammatory effects occur late and are ER stress responses mediated by IRE1a/ASK1/p38 MAPK signaling under conditions of marked cholesterol depletion. rHDL infusions in hypercholesterolemic atherosclerotic mice produced moderate anti-inflammatory effects in lesional macrophages without pro-inflammatory gene expression changes suggesting a beneficial therapeutic effect of HDL in vivo.
2020-04-04 | GSE129347 | GEO
Project description: Not available
| S-EPMC8784167 | biostudies-literature
Project description:Anti-inflammatory effects of HDL in macrophages predominate over pro-inflammatory effects in atherosclerotic plaques
| PRJNA530992 | ENA
Project description:A transcriptome study in mouse hematopoietic stem cells was performed using a sensitive SAGE method, in an attempt to detect medium and low abundant transcripts expressed in these cells. Among a total of 31,380 unique transcript, 17,326 (55%) known genes were detected, 14,054 (45%) low-copy transcripts that have no matches to currently known genes. 3,899 (23%) were alternatively spliced transcripts of the known genes and 3,754 (22%) represent anti-sense transcripts from known genes.
2009-05-20 | GSE16139 | GEO
Project description: Not available
| S-EPMC395764 | biostudies-literature
Project description: Not available
| S-EPMC4490682 | biostudies-literature
Project description: Not available
| S-EPMC5728457 | biostudies-literature
Project description:Background: High density lipoprotein (HDL) protects the artery wall by removing cholesterol from lipid-laden macrophages. However, recent evidence suggests that it might also inhibit atherogenesis by combating inflammation. Methods and Results: To identify potential anti-inflammatory mechanisms, we challenged macrophages with lipopolysaccharide (LPS), an inflammatory microbial ligand for Toll-like receptor 4 (TLR4). HDL inhibited the expression of 33% (301 of 911) of the genes normally induced by LPS, microarray analysis revealed. One of its major targets was the type I interferon response pathway, a family of potent viral immunoregulators controlled by TLR4 and the TRAM/TRIF signaling pathway. Unexpectedly, HDL’s ability to inhibit gene expression was independent of cellular cholesterol stores. Moreover, it was unaffected by downregulation of two ATP-binding cassette transporters, ABCA1 and ABCG1, that promote cholesterol efflux. To examine the pathway’s potential in vivo relevance, we used mice deficient in apolipoprotein (apo) A-I, HDL’s major protein. After infection with Salmonella (a Gram-negative bacterium that expresses LPS), apoA-I–deficient mice had 6-fold higher plasma levels of interferon-beta-a key regulator of the type I interferon response than did wild-type mice. Conclusions: HDL inhibits a subset of LPS-stimulated macrophage genes that regulate the type I interferon response, and its action is independent of sterol metabolism. These findings raise the possibility that regulation of macrophage genes by HDL might link innate immunity and cardioprotection. 12 arrays, 3 experimental groups, mMncN (no treatment), mMncL (LPS treated, exposed for 4 h to serum-free medium or serum-free medium supplemented with 100 ng/mL of LPS), and mMwtL (HDL treated, Macrophages were treated for 4 h with serum-free medium or serum-free medium supplemented with 50 mg/mL of HDL, washed twice with PBS).
2010-10-01 | E-GEOD-19340 | biostudies-arrayexpress