Effect of simultaneous activation of TGFbeta and TLR4 pathway in human monocytes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE17909 | GEO | 2012/12/15
SECONDARY ACCESSION(S): PRJNA119983
REPOSITORIES: GEO
Similar Datasets
Project description:To better understand the interaction of TGFbeta and Toll-like-receptor 4 (TLR4) signaling in monocytes, we performed microarray analysis. We identified a unique set of genes whose expressions in monocytes were regulated by simultaneous stimulation of TLR4 and TGFβ signaling. THP-1 cells, a human monocytic cell line, were stimulated for 24 hours with PBS as control, LPS (100ng/ml), TGFbeta1 (1ng/ml) or LPS (100ng/ml) + TGFbeta1 (1ng/ml). After 24 hours of stimulation, total RNA was isolated and prepared for genome wide analyses using Illumina HumanRef8 V3.0 Beadchips. In total 32 arrays were analyzed including 8 samples of PBS-stimulated monocytes, 8 samples of LPS-stimulated monocytes, 8 samples of TGFbeta1 stimulated monocytes and 8 samples of monocytes stimulated with LPS + TGFbeta1.
2012-12-15 | E-GEOD-17909 | biostudies-arrayexpress
Project description:Among the diseases caused by Toll-like receptor 4 (TLR4) abnormal activation by bacterial endotoxin, sepsis is the most dangerous one. The reprogramming of macrophages plays a crucial role in orchestrating the pathogenesis of sepsis. However, the precise mechanism underlying TLR4 activation in macrophages remained incompletely understood. Our studies revealed that upon lipopolysaccharide (LPS) stimulation, CREB-binding protein (CBP) was recruited to the TLR4 signalosome complex and resulted in pronounced acetylation in the TIR domains of TLR4, Myeloid differentiation factor 88 (MyD88) and MyD88 adapter-like (MAL), which significantly enhanced the activation of the NF-κB signaling pathway and polarization of M1 macrophages. In sepsis patients, significantly elevated TLR4-TIR acetylation was detected in CD16+ monocytes combined with elevated expression of M1 macrophage markers and production of pro-inflammatory cytokines. In contrast, histone deacetylase 1 (HDAC1) served as a key deacetylase in the deacetylation of the TIR domain complex. The inhibition of HDAC1 accelerated sepsis-associated syndromes, while the inhibition of CBP alleviated this process. Overall, our findings highlighted the crucial role of TIR domain complex acetylation in the regulation of inflammatory immune response and suggested that the reversible acetylation of the complex emerged as a promising therapeutic target for M1 macrophages during the progression of sepsis.
2024-08-01 | PXD052433 | Pride
Project description:The toll-like receptor 4 (TLR4) is a central regulator of innate immune signaling that primarily recognizes bacterial lipopolysaccharide (LPS) cell wall constituents to trigger cytokine secretion. We identify the intramembrane protease RHBDL4 as a negative regulator of TLR4 signaling. We show that RHBDL4-triggers the degradation of TLR4’s trafficking factor TMED7, a member of the p24 family of COPII adaptor proteins, which counteracts the transport of TLR4 to the cell surface. Besides TMED7, RHBDL4 cleaves a subset of related p24 cargo receptors, suggesting that this is a general protein abundance control mechanism to regulate the loading of specific secretory proteins into COPII vesicles. Notably, TLR4 activation by LPS mediates transcriptional upregulation of RHBDL4. Hence, TLR4 activation triggers an RHBDL4-dependent negative feedback loop to reduce the export of newly synthesized TLR4 molecules from the endoplasmic reticulum into COPII-coated vesicles. This secretory cargo tuning mechanism prevents the over-activation of TLR4-dependent signaling and consequently alleviates septic shock in a mouse model.
2024-01-09 | PXD045934 | Pride
Project description:The model was constructed to describe TLR4 induced NF-κB activation in native bone marrow-derived macrophages. It included processes of ligand (lipopolysaccharide) recognition, formation of dimer receptor complex and further signal transduction through TRAF6/TAK1 complex that leads to the activation of IKKα/β kinase, which in turn enables the NF-κB transcription factor phosphorylation and translocation in the cell nucleus, and induction of IkB and WIP1 (as an example of induced protein that promotes NF-κB dephosphorylation 2) gene transcription. Models were based on the current knowledge of TLR signaling framework, protein interactions within the TLR4 pathway, and up-to-date mathematical models describing Toll receptor activation.
The major important additions were made to TLR4 signaling description:
1) Receptor dimerization process
2) The existence of a basal nuclear NF-κB level (translocation)
3) NF-κB phosphorylation by IKK complex
2019-03-27 | MODEL1809230001 | BioModels
Project description:The alarmins myeloid-related protein (MRP) 8 and MRP14 are the dominant cytoplasmic proteins in phagocytes. After release by activated phagocytes extracellular MRP8/MRP14 complexes promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis or inflammatory bowel disease. As receptors for the pro-inflammatory effects of human MRP8, the active component of the MRP8/MRP14-complex, Toll-like receptor (TLR) 4 and the multi-ligand receptor of advanced glycation end products (RAGE) are controversial discussed. Using a comparative bioinformatics analysis between genome-wide response patterns of monocytes to MRP8, endotoxin and different cytokines we demonstrated a dominant role of TLR4 during MRP8-mediated phagocyte activation. The relevance of this signaling pathway could be confirmed in independent cell models for TLR4 and RAGE dependent signaling in mouse and man. In addition to well-known proinflammatory functions of MRP8 our systems biology approach unraveled a novel anti-apoptotic effect of MRP8 on monocytes which was confirmed in independent functional experiments. Our data define the dominance of the TLR4-MRP8 axis in activation of human phagocytes which represents a novel attractive target for modulation of overwhelming innate immune responses. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during this process. Human blood monocyte stimulated with various stimuli (control, MRP8, LPS, TNF, IL1) were selected for RNA extraction and hybridization on Affymetrix microarrays.
2014-12-12 | E-GEOD-56681 | biostudies-arrayexpress
Project description:Sensing of pathogens by Toll-like receptor 4 (TLR4) induces an inflammatory response; controlled responses confer immunity but uncontrolled responses cause harm. Here we define how a multi-modular scaffold, GIV (a.k.a Girdin) titrates such inflammatory response in macrophages. Upon challenge with microbe-derived lipopolysaccharides (LPS, a ligand for TLR4), macrophages with GIV mount a more tolerant (hypo-reactive) transcriptional response and suppress pro-inflammatory cytokines and signaling pathways (i.e., NFkB and CREB) downstream of TLR4 compared to their GIV-depleted counterparts.
2020-07-08 | GSE153924 | GEO
Project description:Toll-like receptor 4 (TLR4) sensing of lipopolysaccharide (LPS), the most potent pathogen-associated molecular pattern of gram-negative bacteria, activates NF-κB and Irf3, which induces inflammatory cytokines and interferons that trigger an intense inflammatory response, which is critical for host defense but can also cause serious inflammatory pathology, including sepsis. Although TLR4 inhibition is an attractive therapeutic approach for suppressing overexuberant inflammatory signaling, previously identified TLR4 antagonists have not shown any clinical benefit. Here, we identify disulfiram (DSF), an FDA-approved drug for alcoholism, as a specific inhibitor of TLR4-mediated inflammatory signaling. TLR4 cell surface expression, LPS sensing, dimerization and signaling depend on TLR4 binding to MD-2. DSF and other cysteine-reactive drugs, previously shown to block LPS-triggered inflammatory cell death (pyroptosis), inhibit TLR4 signaling by covalently modifying Cys133 of MD-2, a key conserved residue that mediates TLR4 sensing and signaling. DSF blocks LPS-triggered inflammatory cytokine, chemokine, and interferon production by macrophages in vitro. In the aggressive N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease (PD) in which TLR4 plays an important role, DSF markedly suppresses neuroinflammation and dopaminergic neuron loss, and restores motor function. Our findings identify a role for DSF in curbing TLR4-mediated inflammation and suggest that DSF and other drugs that target MD-2 might be useful for treating PD and other diseases in which inflammation contributes importantly to pathogenesis.
2023-08-07 | GSE237028 | GEO
Project description:We here identified that the trimeric spike protein of SARS-CoV-2 could bind to TLR4 directly and robustly activate downstream signaling in monocytes and neutrophils. Moreover, specific TLR4 or NFKB inhibitor, or knockout of MyD88 could significantly block IL-1B induction by spike protein. We thus reveal that spike protein of SARS-CoV-2 functions as a potent stimulus causing TLR4 activation and sepsis related abnormal responses.
2021-02-25 | GSE167480 | GEO
Project description:Peroxiredoxin 1 (PRDX1), traditionally known as an intracellular antioxidant enzyme, has emerged as a regulator of inflammatory responses via Toll-like receptor 4 (TLR4) signaling. Despite this, the mechanistic details of the PRDX1-TLR4 axis and its impact on osteoclast differentiation remain elusive. Here, we show that PRDX1 suppresses RANKL-induced osteoclast differentiation. Utilizing pharmacological inhibitors, we reveal that PRDX1 inhibits osteoclastogenesis through both TLR4/TRIF and TLR4/MyD88 pathways. Transcriptome analysis revealed PRDX1-mediated alterations in gene expression, particularly upregulating serum amyloid A3 (SAA3) and aconitate decarboxylase 1 (ACOD1), known inhibitors of osteoclast differentiation. Mechanistically, PRDX1-TLR4 signaling activates p65, promoting SAA3 and ACOD1 expression while inhibiting NFATc1, a master regulator of osteoclastogenesis. Remarkably, PRDX1 redirects p65 binding from NFATc1 to SAA3/ACOD1 promoters, thereby suppressing osteoclast formation. Structural analysis showed that monomeric variants of PRDX1 with enhanced TLR4 binding exhibit potent inhibition of osteoclast differentiation. Our findings elucidate the inhibitory role of PRDX1-TLR4 axis in osteoclastogenesis, providing insights into therapeutic strategies for bone-related disorders.
2024-11-12 | GSE267039 | GEO
Project description:Although abnormal TGFbeta signaling is observed in several heritable forms of thoracic aortic aneurysms and dissections including Marfan syndrome, the precise role of TGFbeta signaling in aortic disease progression is still disputed. Using a mouse genetic approach and quantitative isobaric labeling proteomics, we sought to investigate the role of TGFbeta signaling in molecular pathways of pathogenesis associated with development of aortic aneurysm and aortic rupture. This study reports an isoform-specific effect of TGFbeta in MFS aortic disease and the effects of deleting the first hybrid domain of fibrillin-1 on TGFbeta signaling. Distinct molecular differences in mouse models of aneurysm (Fbn_GT-8_plus), of aneurysm and rupture (Fbn1_GT-8_H1delta), and of microdissection (Fbn1_H1delta_plus) were identified, which associated with TGFbeta signaling and extracellular matrix composition, possibly contributing to the development of dissection and rupture. These findings offer new insights into the pathophysiological mechanisms that potentially drive initiation of aortic dissection and could pave the way for development of new treatment targets of aortic disease.
2023-10-09 | PXD036222 | Pride