Olfr2-positive macrophages originating from monocytes proliferate in situ and present a pro-inflammatory foamy-like phenotype
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE325044 | GEO | 2026/03/31
REPOSITORIES: GEO
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Project description:Olfr2-positive macrophages originating from monocytes proliferate in situ and present a pro-inflammatory foamy-like phenotype
| PRJNA1438280 | ENA
Project description:Atherosclerosis-associated vascular disease is the leading cause of death worldwide. Clinical and experimental data demonstrated that circulating monocytes internalize plasma lipoproteins and become lipid-laden foamy cells in hypercholesterolemic subjects. This study was designed to identify the endocytic mechanisms responsible for foamy monocyte formation, perform functional and transcriptomic analysis of foamy and non-foamy monocytes, and characterize specific monocyte subsets in the circulation from normocholesterolemic controls and hypercholesterolemic patients. The presence of foamy monocytes was confirmed in hypercholesterolemic mice and humans via flow cytometry analysis. High resolution scanning electron microscopy (SEM) and quantification of FITC/TRITC-dextran internalization demonstrated macropinocytosis stimulation in human (THP-1) and wild type murine monocytes in vitro. Stimulation of macropinocytosis induced foamy monocyte formation in the presence of unmodified, native LDL (nLDL) and oxidized LDL (ox-LDL) in vitro. Genetic blockade of macropinocytosis (LysMCre+ Nhe1f/f) inhibited foamy monocyte formation in hypercholesterolemic mice in vivo and attenuated monocyte adhesion to atherosclerotic aortas ex vivo. qRT-PCR quantified mRNA levels of major scavenger receptors (SR) in foamy and non-foamy monocytes and identified CD36 as a major SR increasing in response to lipid loading. Deletion of CD36 (Cd36-/-) inhibited foamy monocyte formation in hypercholesterolemic mice. Mechanistic studies identified NADPH oxidase 2 (Nox2)-derived superoxide (O2⋅−) as an important downstream signaling molecule stimulating macropinocytosis in monocytes. Bulk RNA-sequencing characterized transcriptional differences between non-foamy and foamy monocytes and macrophages. Flow cytometry analysis of CD14 and CD16 expression demonstrated a significant increase in intermediate monocytes in hypercholesterolemic patients compared to normocholesterolemic controls. These results provide novel insights into the mechanisms of foamy monocyte formation and potentially identify new therapeutic targets in the treatment of atherosclerosis.
2024-12-26 | GSE278101 | GEO
Project description:Formation of foam cell macrophages (FCMs), which sequester extracellular modified lipids, is a key event in atherosclerosis. How lipid loading affects macrophage phenotype is controversial, with evidence suggesting either pro- or anti-inflammatory consequences. To investigate this further, we compared the transcriptomes of foamy and non-foamy macrophages (NFMs) that accumulate in the subcutaneous granulomas of fed-fat ApoE null mice and normal chow fed wild-type mice in vivo. Consistent with previous studies, LXR/RXR pathway genes were significantly over-represented among the genes up-regulated in foam cell macrophages. Unexpectedly, the hepatic fibrosis pathway, associated with platelet derived growth factor and transforming growth factor-? action, was also over-represented. Several collagen polypeptides and proteoglycan core proteins as well as connective tissue growth factor and fibrosis-related FOS and JUN transcription factors were up-regulated in foam cell macrophages. Increased expression of several of these genes was confirmed at the protein level in foam cell macrophages from subcutaneous granulomas and in atherosclerotic plaques. Moreover, phosphorylation and nuclear translocation of SMAD2, which is downstream of several transforming growth factor-? family members, was also detected in foam cell macrophages. We conclude that foam cell formation in vivo leads to a pro-fibrotic macrophage phenotype, which could contribute to plaque stability, especially in early lesions that have few vascular smooth muscle cells. Samples (n=4/group): Foam cell macrophages (FCM) isolated from inflammatory sponges placed in ApoE null mice fed a high-fat diet (n=4), non-foamy macrophages (NFM) isolated from inflammatory sponges placed in control mice fed a normal diet (n=4).
2015-07-23 | E-GEOD-70126 | biostudies-arrayexpress
Project description:The priming of blood monocytes and the infiltration of monocyte-derived macrophages into the vessel walls are the central part of atherosclerosis. However, the mechanisms underlying the processes remain unclear. Here we report that G-protein-signaling modulator 1 (GPSM1) plays a critical role in atherogenesis. We found that GPSM1 expression in lesional macrophages was increased during atherosclerosis development both in mice and human. Myeloid-specific GPSM1 ablation protects mice against atherosclerosis and reduces aortic inflammation, in both Apoe-/- mice and an AAV-PCSK9 injection model. Conversely, myeloid-restricted overexpression of GPSM1 accelerates aortic inflammation and promotes atherosclerosis development in mice. Mechanistically, GPSM1 deficiency suppressed monocyte priming including chemotaxis and adhesion through inhibition of p38/ERK MAPK pathway regulated by cAMP/PKA/KLF4/PMP22 axis, thereby alleviating pro-inflammatory responses within atherosclerotic plaques. Blockade of PMP22 using siRNA-loaded liposomes protected GPSM1 overexpression mice from atherosclerosis. Furthermore, a small-molecule compound inhibiting GPSM1 function could suppress atherosclerosis in vivo. In conclusion, our findings establish that GPSM1 is a novel regulator of atherosclerosis development and targeting GPSM1 might be a promising therapy against atherosclerosis.
2025-08-19 | GSE305743 | GEO
Project description:Formation of foam cell macrophages (FCMs), which sequester extracellular modified lipids, is a key event in atherosclerosis. How lipid loading affects macrophage phenotype is controversial, with evidence suggesting either pro- or anti-inflammatory consequences. To investigate this further, we compared the transcriptomes of foamy and non-foamy macrophages (NFMs) that accumulate in the subcutaneous granulomas of fed-fat ApoE null mice and normal chow fed wild-type mice in vivo. Consistent with previous studies, LXR/RXR pathway genes were significantly over-represented among the genes up-regulated in foam cell macrophages. Unexpectedly, the hepatic fibrosis pathway, associated with platelet derived growth factor and transforming growth factor-β action, was also over-represented. Several collagen polypeptides and proteoglycan core proteins as well as connective tissue growth factor and fibrosis-related FOS and JUN transcription factors were up-regulated in foam cell macrophages. Increased expression of several of these genes was confirmed at the protein level in foam cell macrophages from subcutaneous granulomas and in atherosclerotic plaques. Moreover, phosphorylation and nuclear translocation of SMAD2, which is downstream of several transforming growth factor-β family members, was also detected in foam cell macrophages. We conclude that foam cell formation in vivo leads to a pro-fibrotic macrophage phenotype, which could contribute to plaque stability, especially in early lesions that have few vascular smooth muscle cells.
2015-07-23 | GSE70126 | GEO
Project description:Atherosclerosis is the major cause of death in industrialized countries. This disease has initially been characterized as a lipid disorder, but current concepts argue for an inflammatory disease, which develops in the background of hypercholesterolemia and other risk factors. In response to initial events of atherosclerosis formation, such as LDL-deposition in the subendothelial space, monocytes and T cells interact with the vessel wall. However, little is known about the properties and the behavior of these cells in this context. Using familial hypercholesterolemia (FH) as a model we demonstrate substantial differences in the gene expression of freshly isolated human monocytes and T lymphocytes. In FH monocytes we found an increased uptake of oxidized LDL, elevated amounts of scavenger receptors and adhesion molecules, and differences in the regulation of intracellular lipoprotein metabolism compared to monocytes from healthy individuals. Furthermore, the monocyte subpopulation of CD14+/CD16+ cells is less frequent in FH but exhibits significantly higher levels of CD11c and CD29 which increases the likelihood for their transmigration through the endothelial layer. The presence of increased amounts of CD69 in T lymphocytes from FH patients suggests that these cells are more activated than control cells. Our results indicate that some important steps of atherosclerosis formation already take place in circulating blood cells which extends current atherosclerosis models to the plasma compartment. Keywords: atherosclerosis, T cells, Familial Hypercholesterolemia
2008-04-01 | GSE6088 | GEO
Project description:Atherosclerosis is the leading cause of heart attack and stroke worldwide. The key characteristic of atherosclerosis is accumulation of LDL cholesterol in artery walls, subsequent infiltration by monocytes/macrophages, and development of inflammation. Macrophage-driven inflammation causes oxidative stress, thereby enhancing endothelial cell activation, immune cell recruitment, and foam cell formation. Lowering LDL plasma levels, as well as inhibiting inflammation, reduces the risk of cardiovascular events. Recently, we reported that plasma protein complement factor H-related 1 (FHR1) binds to the necrotic surfaces of cardiovascular plaques and induces inflammation driven by monocytes/macrophages and neutrophilic granulocytes. Moreover, the concentration of FHR1 is higher, whereas CFHR1 gene deletion frequency is significantly lower, in patients with atherosclerosis than in healthy controls. To investigate the link between FHR1 and atherosclerosis, we generated FHRE-/- (the murine homolog of FHR1) knockout mice and then crossed them with ApoE-/- knockout mice (a model of human atherosclerosis). Notably, deletion of FHRE enhanced lipid degradation in liver as seen by RNAseq analysis, resulting in normalized cholesterol levels, reduced inflammation and no plaque formation in FHRE-/-ApoE-/- mice than in ApoE-/- mice expressing FHRE. These data indicate that FHRE directs uptake of oxLDL by macrophages, and supports foam cell formation, plaque development, and inflammation in dislipidemic mice. As human FHR1 correlates with non-HDL cholesterol concentrations and inflammation markers in patients with atherosclerosis-associated cardiovascular disease (ACVD) we assume that FHR1/FHRE plays a key role in development of atherosclerosis and subsequent events such as stroke and heart attack.
2026-01-28 | GSE272153 | GEO
Project description:To examine mononuclear cell gene expression profiles in patients with and without SLE and subsets with and without atherosclerosis Monocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro differentiated into macrophages. Subjects also underwent laboratory and imaging studies of the coronary arteries, carotid arteries, and aorta to evaluate for subclinical atherosclerosis.
2012-04-16 | E-GEOD-37356 | biostudies-arrayexpress
Project description:Monocytes and T-cells play an important role in the development of atherosclerotic coronary artery disease (CAD). Differences in transcriptional activity of these cells might reflect the individual's atherosclerotic burden. Transcriptome analysis of circulating mononuclear cells from carefully matched atherosclerotic and control patients will potentially provide insights into the pathophysiology of atherosclerosis and supply biomarkers for diagnostic purposes. From patients undergoing coronary angiography because of anginal symptoms, we carefully matched 18 patients with severe triple-vessel CAD to 13 control patients without signs of CAD on angiography. All patients were on statin and aspirin treatment. RNA from circulating CD4+ T-cells, CD14+ monocytes, lipopolysaccharide-stimulated monocytes, macrophages and CD34+ progenitor cells was subjected to genome-wide expression analysis. Only CD14+ monocytes demonstrated that a small number of genes involved in activation was overexpressed in control patients, which was verified by real-time polymerase-chain reaction. In this pilot study, cautious matching of patients with severe atherosclerotic CAD with control patients without angiographic signs of coronary atherosclerosis did not reveal differences in transcriptional activity in four out of five different mononuclear cell types. In resting monocytes from patients without overt CAD some inflammatory genes were overexpressed as compared to patients with severe CAD. Large inter-individual variability prevented the use of single differentially expressed genes as biomarkers. Keywords: disease-state analysis In total 153 arrays were analyzed with 6 technical replicates (147 biological samples). CD34+ stem cells, CD4+ T-cells, resting CD14+ monocytes, stimulated monocytes and macrophages were analyzed, all from patient with severe coronary atherosclerosis or controls that had no coronary atherosclerosis as determined angiographically, and which were carefully matched for age and gender.
2008-12-01 | E-GEOD-9820 | biostudies-arrayexpress
Project description:Background and Aims Aging is the primary risk factor for cardiovascular disease (CVD), but the mechanisms underlying age-linked atherosclerosis remain unclear. We previously observed that long-lived vascular matrix proteins can acquire ‘gain-of-function’ isoDGR motifs that might play a role in atherosclerotic pathology. Methods: IsoDGR-specific mAb were generated and used for ELISA-based measurement of motif levels in plasma samples from patients with coronary artery diseases (CAD) and non-CAD controls. Functional consequences of isoDGR accumulation in age-damaged fibronectin were determined by bioassay for capacity to activate monocytes, macrophages, and endothelial cells (signalling activity, pro-inflammatory cytokine expression, and recruitment/adhesion potential). Mice deficient in the isoDGR repair enzyme PCMT1 were used to assess motif distribution and macrophage localisation in vivo. Results: IsoDGR-modified fibronectin and fibrinogen levels in patient plasma were significantly enhanced in CAD and further associated with smoking status. Functional assays demonstrated that isoDGR-modified fibronectin activated both monocytes and macrophages via integrin receptor ‘outside in’ signalling, triggering an ERK:AP-1 cascade and expression of pro-inflammatory cytokines MCP-1 and TNF to drive additional recruitment of circulating leukocytes. IsoDGR-modified fibronectin also induced endothelial cell expression of integrin 1 to further enhance cellular adhesion and matrix deposition. Analysis of murine aortic tissues confirmed accumulation of isoDGR-modified proteins co-localised with CD68+ macrophages in vivo. Conclusions: Age-damaged fibronectin features isoDGR motifs that increase binding to integrins on the surface of monocytes, macrophages, and endothelial cells. Subsequent activation of ‘outside-in’ signalling elicits a range of potent cytokines and chemokines that drive additional leukocyte recruitment to the developing atherosclerotic matrix.
2022-10-25 | PXD024380 | Pride