Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Local restriction of sterile inflammation by auto-inhibitory regulation of S100A8/S100A9-alarmin activity

ABSTRACT: Autoimmune diseases, like psoriasis or arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals like Danger-Associated Molecular Pattern molecules (DAMPs) are indispensable for manifestation of local inflammation. S100A8/100A9-complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP-activities are barely understood. We now unravel for the first time a novel mechanism of auto-inhibition in mice and man restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry and targeted mutations we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9-heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9-activities are locally restricted by calcium-induced (S100A8/S100A9)2-tetramer formation now hiding the TLR4/MD2-binding site within the tetramer interphase thus preventing undesirable systemic effects. Loss of this auto-inhibitory mechanism in vivo results in TNFa-driven fatal inflammation as shown by lack of tetramer formation crossing S100A9-/- mice with two independent TNFa-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking of the TLR4-binding site of active S100-dimers represents an innovative approach for local suppression of inflammatory diseases avoiding systemic side effects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109426 | GEO | 2019/04/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Expression data for murine colon carcinoma cell line CT26.WT stimulated with S100a8 or S100a9 recombinant protein

Project description:Damage-associated molecular pattern (DAMP) molecules S100A8 and S100A9 with well-known functions in inflammation, tumor growth and metastasis. It has been found to have promote tumor cell proliferation activity at low concentration . However, the mechanism underlying this remains unclear. In the current study, we performed genome expression profiling analysis using the Affymetrix genome wide microarray system to identify broad scale changes in gene expression associated with S100a8 or S100a9 recombinant protein stimulation in murine colon carcinoma cell line CT26.WT.

2015-11-29 | GSE53735 | GEO

S100A8/A9 induced by interaction with macrophages in esophageal squamous cell carcinoma promotes the migration and invasion of cancer cells via Akt and p38 MAPK pathways

Project description:Tumor-associated macrophages enhance the malignant phenotypes of esophageal squamous cell carcinoma (ESCC) cells. We have previously identified several factors associated with ESCC progression using an indirect co-culture assay between ESCC cells and macrophages. Here, we newly established a direct co-culture assay between ESCC cells and macrophages which is closer to the actual cancer microenvironment than an indirect co-culture assay. To investigate the gene expression changes by co-culture with macrophages, we performed cDNA microarray analysis between mono-cultured and co-cultured ESCC cells with macrophages. We found that the expression of S100 calcium binding protein A8 and A9 (S100A8 and S100A9) was enhanced in co-cultured ESCC cells with macrophages. S100A8 and S100A9 commonly exist stable and function as a heterodimer (S100A8/A9). S100A8/A9 is widely known as an inflammation marker. It also contributes to the enhancement of malignant phenotypes in several cancers. S100A8/A9 enhances the migration and invasion of ESCC cells by activating Akt and p38 MAPK signaling pathways. The higher expression levels of S100A8/A9 were associated with poor prognosis in ESCC patients. These results suggest that S100A8/A9 contributes to the progression of ESCC.

2021-12-01 | GSE174796 | GEO

A proteome-wide screen identifies the calcium binding proteins, S100A8/S100A9, as clinically relevant therapeutic targets in aortic dissection: a translational study [scRNA-seq]

Project description:S100A8 and S100A9 (aliases MRP8 and MRP14) are highly expressed in neutrophils and monocytes and are classified as damage-associated molecular pattern (DAMP) molecules or alarm molecules. However, the role of S100A8/A9 in aortic dissection has not been reported. In the present study, by employing an unbiased proteomics approach and RNA sequencing analysis , we found that the protein expression of calcium binding proteins S100A8/A9 were upregulated in the aorta and serum of TAAAD patients and also in a mouse model.

2024-05-06 | GSE247260 | GEO

Expression data from S100A9 and HMGB1 treated human CD14+ monocytes

Project description:TLR4 signaling was reported to be involved in the upregulation of PD-L1 expression and induction of immunosuppressive properties of human CD14+ monocytes. Damage associated molecular patterns (DAMPs) S100A8, A9, and HMGB1, which act as endogenous TLR4 ligands, drive MDSC activation and were shown to be markedly expressed in the tumor microenvironment (TME) of solid tumors. The role of S100A8/9 and HMGB1 in the acquisition of MDSC immunosuppressive activity remains to be better defined.

2024-07-19 | GSE254271 | GEO

Transcriptomic changes in macrophages induced by damage-associated molecular patterns (DAMPs)

Project description:Dead cell-derived molecules, typically called as damage-accociated molecular patterns (DAMPs), have been shown to evoke inflammatory responses. Accordingly, it becomes increasingly clear that DAMPs play important role in pathogenesis of multiple diseases including inflammatory diseases and cancer. To get a comprihensive view of DAMP-mediated inflammatory responses, we perfomed microarray analysis on murine macrophages treated by dead cell-derived molecules.

2021-05-21 | GSE150465 | GEO

Single cell gene expression profile of bronchoalveolar lavage fluid (BALF) cells from Apoa1-/- and Apoa1+/+ mice challenged with LPS and house dust mite

Project description:Neutrophils play important roles in inflammatory airway diseases. Here, we assessed whether apolipoprotein A-I (apoA-I) modifies neutrophil heterogeneity as part of the mechanism by which it attenuates acute airway inflammation. Neutrophilic airway inflammation was induced by daily intranasal administration of LPS plus house dust mite (LPS+HDM) to Apoa1-/- and Apoa1+/+ mice for 3 days. Single cell RNA sequencing was performed on cells recovered in bronchoalveolar lavage fluid (BALF) on day 4. Unsupervised profiling identified 10 clusters of neutrophils in BALF from Apoa1-/- and Apoa1+/+ mice. LPS+HDM-challenged Apoa1-/- mice had an increased proportion of the Neu4 neutrophil cluster that expressed S100a8, S100a9, and Mmp8, and had high maturation, aggregation, and TLR4 binding scores. There was also an increase in the Neu6 cluster of immature neutrophils, whereas neutrophil clusters expressing interferon-stimulated genes were decreased. An unsupervised trajectory analysis showed that Neu4 represented a distinct lineage in Apoa1-/- mice. LPS+HDM-challenged Apoa1-/- mice also had an increased proportion of recruited airspace macrophages, which was associated with a reciprocal reduction in resident airspace macrophages. Increased expression of a common set of pro-inflammatory genes, S100a8, S100a9, and Lcn2, was present in all neutrophils and airspace macrophages from LPS+HDM-challenged Apoa1-/- mice. Apoa1-/- mice have increases in specific neutrophil and macrophage clusters in the lung during acute inflammation mediated by LPS+HDM, as well as enhanced expression of a common set of pro-inflammatory genes. This suggests that modifications in neutrophil and macrophage heterogeneity contribute to the mechanism by which apoA-I attenuates acute airway inflammation.

2024-07-29 | GSE234287 | GEO

Setd2 deficiency impaired erythroid differentiation and accelerated Myelodysplastic Syndrome(MDS) - associated leukemogenesis through S100A8 and S100A9

Project description:Setd2, the histone H3 lysine 36 methyltransferase, plays an important role in the pathogenesis of hematologic malignancies. The research on the role of Setd2 in leukemogenesis has made great progress, but its role in MDS is still unknown. Here, we knock out Setd2 in the NUP98-HOXD13 transgenic (NHD13 Tg) mouse, and demonstrate that loss of Setd2 accelerates the transformation of MDS into AML. The conditional deletion of Setd2 also interferes the differentiation of hematopoietic stem and progenitor cells (HSPCs), and results in the decrease of granulocyte monocyte progenitor (GMP) cells, increase of megakaryocyte erythroid progenitor (MEP) cells and common myeloid progenitor (CMP) cells. Loss of Setd2 impairs erythroid differentiation, includes cell cycle arrest in G2-M and enhances the selt-renewal ability of HSPCS. Our RNA-seq,ChIP-seq and WGBS analysis indicats that S100A8 and S100A9 are direct target genes of H3K36me3 and expression of heterodimeric S100 calcium-binding proteins S100A8 and S100A9 are downregulated in HSPCs when Setd2 deficiency. Addition of recombinant S100A8 or S100A9 weakens the clonogenic progenitors of Setd2 deficient HSPCs. Therefore, our results demonstrate that loss of Setd2 promotes the transformation of MDS into AML, which proves Setd2 as a tumor suppressor in MDS, and provides a potential therapeutic target for MDS associated leukemia.

2020-07-02 | GSE129691 | GEO

Expression data of GMDCs with conditioned medium from topotecan-treated E0771 cells

Project description:Danger-associated molecular patterns (DAMPs) derived from damaged or dying cells not only elicit inflammation but also potentiate antitumor immune responses. Here, we show that treatment of breast cancer cells with the antitumor agent Topotecan, an inhibitor of topoisomerase I, induces DAMP secretion that triggers dendritic cell activation and cytokine production.

2016-12-01 | GSE90042 | GEO

S100A8 treatment on gene expression of human umbilical vascular endothelial cells.

Project description:Previous studies showed that S100A8 and S100A9 are involved in neovascularization as well as in tumor development. At high concentrations, S100A8 and S100A9 cause inflammatory response or apoptosis mediated damage in vascular endothelial cells. But the effect of low concentrations of such proteins on endothelial cells remains unknown. This assay was performed to screen for genes that are involved in the response of Human Unbilican Vascular Endothelial Cells to low concentrations of S100A8. Human Umblical Vascular Endothelial Cells (HUVEC) were cultuered and treated with 10ug/mL S100A8 proteins for 4 or 24 hours. Gene profiling was carried out using two-color microarray. Two-condition experiment, S100A8 treatment vs. non-treatment. Two time points: 4 hours and 24 hours. Biological replicates at each time point: 3 control replicates, 3 treatment replicates.

2011-11-20 | E-GEOD-33768 | biostudies-arrayexpress

Human melanoma-derived extracellular vesicles reprogram dendritic cells potentially enabling lymph node metastases

Project description:Evolution of melanoma from a primary tumor to widespread metastasis is crucially dependent on lymphatic spread. The mechanisms regulating the initial step in metastatic dissemination via regional lymph nodes remain largely unknown. We have previously described a dysfunctional immune profile that precedes evidence of metastasis in the first node draining from the primary tumor, the sentinel lymph node (SLN). Herein, we explore the role of melanoma-derived extracellular vesicles (EVs) as mediators of this pre-metastatic niche through cargo-specific polarization of dendritic cells (DCs). Utilizing mass cytometry, pre-metastatic SLNs demonstrate compromised co-stimulatory CD80 expression compared to healthy lymph nodes. Similarly, DCs matured in vitro in the presence of melanoma EVs showed impaired co-stimulation and polarization towards a chronic inflammatory cytokine milieu. Profiling of melanoma EV cargo identified shared proteomic and RNA signatures including the signaling axis S100A8, S100A9 and cognate receptor TLR4. Mechanistically, S100A8 and S100A9 compromised DC maturation, a phenotype which was partially recovered following TLR4 blockade. Early evidence demonstrates similar EVs can be isolated from human afferent lymphatic fluid ex vivo. Taken together, we propose synergistic interactions among melanoma EV cargo are responsible for suppressing DC maturation, potentially explaining the survival of malignant melanocytes metastasizing into seemingly “normal” regional lymph nodes.

2018-10-26 | PXD005539 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data