Expression data from human HEK293 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE35084 | GEO | 2012/01/14
SECONDARY ACCESSION(S): PRJNA150915
REPOSITORIES: GEO
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Project description:LPA, which can signal through the Ga12/13 family of G proteins, is a potent stimulator of fibroblast migration. LPA downregulate mTOR activity dependent on protein synthesis in cell migration and bleomycin-induced lung fibrosis. We used microarray to identify LPA-regualted gene expression and find potent regulators in this process. HEK293 cells were treated with or without LPA. Then RNA was extracted and Hybridization was done on Affymetrix microarrays.
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Project description:Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β1 exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, administration of Ogg1-targetting siRNA, mitigated bleomycin-induced pulmonary fibrosis in mice, thereby highlighting OGG1 as a tractable target in lung fibrosis. The novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation, with both increased in fibrotic murine and IPF patient lung tissue. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF. This DIA-MS dataset entails the raw data and peptide-centric DIA-NN search results of both, lung tissue and bronchoalveolar lavage fluid of n=5 mice profiled across the treatment groups bleomycin combined with TH (BTH), dexamethasone (DEX), TH alone (TH) and vehicle control (V) relative to bleomycin alone (B) as control. Different animals within protein groups were considered biological replicates of the respective treatment condition.
2023-02-06 | PXD029625 | Pride
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2013-07-22 | GSE42564 | GEO
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2017-01-20 | GSE93860 | GEO
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Project description:Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA1, like that of the phospholipase PLA2G3, the prostaglandin D2 (PGD2) synthase L-PGDS, or the PGD2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD2 generation, and feedforward ATX-LPA1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation.
2024-11-12 | GSE253356 | GEO
Project description:Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA1, like that of the phospholipase PLA2G3, the prostaglandin D2 (PGD2) synthase L-PGDS, or the PGD2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD2 generation, and feedforward ATX-LPA1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation.
2024-11-12 | GSE262558 | GEO
Project description:Lysophosphatidic acid (LPA) species, prevalent in the tumor microenvironment (TME), adversely impact various cancers. In ovarian cancer, the 18:0 and 20:4 LPA species in particular are associated with shorter relapse-free survival, indicating distinct effects on cellular signaling networks. Macrophages represent a cell type of high relevance in the TME, but the impact of LPA on them remains obscure. Here, we uncovered distinct LPA-species-specific responses in human monocyte-derived macrophages through unbiased phosphoproteomics, with 87 and 161 phosphosites upregulated by 20:4 and 18:0 LPA, respectively, and only 24 shared sites. Specificity was even more pronounced for downregulated phosphosites (163 versus 5 sites). Considering the frequently high levels of 20:4 LPA in the TME and its association with poor survival, these findings are of relevance for further understanding of cancer promotion and maintenance. Pathway analysis pinpointed RHO/RAC1 GTPase signaling as the predominantly impacted pathway, including AHRGEF and DOCK guanine exchange factors, ARHGAP GTPase activating proteins, and regulatory protein kinases. Consistent with these findings, exposure to 20:4 resulted in strong alterations to the actin filament network and a consequent enhancement of macrophage migration. Moreover, 20:4 LPA induced p38 phosphorylation, a response not mirrored by 20:4 LPA, whereas the pattern for AKT was reversed. Furthermore, RNA profiling identified genes involved in cholesterol/lipid metabolism as selective targets of 20:4 LPA. These findings imply that the two LPA species cooperatively regulate different pathways to support functions essential for pro-tumorigenic macrophages within the TME. These include cellular survival via AKT activation and migration through RHO/RAC1 and p38 signaling.
2024-04-03 | MSV000094459 | MassIVE
Project description:Background: OxPLs play a key role in the atherogenic potential of Lp(a), however Lp(a) is a complex particle that warrants research into additional pro-inflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a). Methods: Untargeted lipidomics was performed on plasma and isolated lipoprotein fractions. The atherogenicity of the observed Lp(a)-associated lipids was tested ex vivo in primary human monocytes by RNAseq, ELISA, Western Blot and transendothelial migratory assays. Using immunofluorescence staining and single-cell RNA sequencing, the phenotype of macrophages was investigated in human atherosclerotic lesions. Results: Compared to healthy individuals with low/normal Lp(a) levels [median 7 mg/dL (18 nmol/L); N=13], individuals with elevated Lp(a) levels [median 87 mg/dL (218 nmol/L); N=12] demonstrated an increase in lipid species, particularly diacylglycerols (DGs) and lysophosphatidic acid (LPA). DG and the LPA precursor lysophosphatidylcholine were enriched in the Lp(a) fraction. Ex vivo stimulation with DG(40:6) demonstrated a significant upregulation in pro-inflammatory pathways related to leukocyte migration, chemotaxis, NF-κB signalling and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL-6, IL-8 and IL-1β after DG(40:6) and DG(38:4) stimulation, which was in part mediated via the NLRP3-inflammasome. Conversely, LPA-stimulated monocytes did not exhibit an inflammatory phenotype. Furthermore, activation of monocytes by DGs and LPA increased their transendothelial migratory capacity. Human atherosclerotic plaques from patients with high Lp(a) levels demonstrated co-localisation of Lp(a) with M1 macrophages, and an enrichment of CD68+IL18+TLR4+TREM2+ resident macrophages and CD68+CASP1+IL1B+SELL+ inflammatory macrophages compared to patients with low Lp(a). Finally, potent Lp(a) lowering treatment (pelacarsen), resulted in a reduction in specific circulating DG lipid subspecies in cardiovascular disease patients with elevated Lp(a) levels [median 82 mg/dL (205 nmol/L)]. Conclusions: Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is in part NLRP3-inflammasome dependent.
2024-01-25 | GSE249911 | GEO