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Expression data from S100A9 and HMGB1 treated human CD14+ monocytes

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254271 | GEO | 2024/07/19

REPOSITORIES: GEO

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

Project description: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.

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S100A8/S100A9 cytokine functions as transcriptional coactivator during breast cellular transformation

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Expression data from S100A9 and HMGB1 treated human CD14+ monocytes

Project description:Expression data from S100A9 and HMGB1 treated human CD14+ monocytes

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Hepatic transcriptome profiles of ethanol-treated mice with HMGB1 knockout in hepatocytes and/or macrophages

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Induction of S100A8/S100A9 mediates the erythroid differentiation block in ribosomal protein S14 haploinsufficiency

Project description:Schneider RK, Schenone M, Kramann R, Ferreira MV, Joyce CE, Hartigan C, Beier F, Brümmendorf TH, Gehrming U, Platzbecker U, Buesche G, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL. Nat Med, 2016. Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100A8/S100A9 proteins in purified erythroblasts. S100A8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100A8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS.

2016-01-26 | MSV000079482 | MassIVE

S100A8/A9 activate key genes and pathways in colon tumor progression

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