The alarmin S100A9 hampers retroviral infection by limiting reverse transcription
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727578 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14434100.fastq.gz | Fastqsanger.gz | |||
| SRR14434101.fastq.gz | Fastqsanger.gz | |||
| SRR14434102.fastq.gz | Fastqsanger.gz | |||
| SRR14434103.fastq.gz | Fastqsanger.gz | |||
| SRR14434104.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:We identified the alarmin S100A9 as a novel intracellular antiretroviral factor expressed in human monocyte-derived and skin-derived Langerhans cells (LC). The expression of S100A9 is significantly upregulated by the transforming growth factor beta in human monocyte-derived cells. We showed that S100A9 intracellular expression is decreased upon maturation and inversely correlated with an enhanced inversely correlates with the maturation level of LC and susceptibilityility to HIV-1 infection of LC. Furthermore, silencing of S100A9 in primary human LC relieves HIV-1 restriction while ectopic expression of S100A9 in various cell lines established an intrinsic resistance to both HIV-1 and MMLV infection by acting on reverse transcription. Mechanistically, the intracellular expression of S100A9 alters viral capsid uncoating and reverse transcription in a distal manner. Also, S100A9 demonstrates potent inhibitory effect against HIV-1 and MMLV reverse transcriptase (RTase) activity in-vitro in a divalent cation-dependent context. Our findings uncover an unexpected intracellular antiretroviral function of the human alarmin S100A9 and highlight a novel crosstalk betweenregulating antiretroviral immunity in Langerhans cells
2021-05-06 | GSE173939 | GEO
Project description:Dendritic cells (DC) subsets, like Langerhans cells (LC), are immune cells involved in pathogen sensing. They express specific antimicrobial cellular factors that are able to restrict infection and limit further pathogen transmission. Here, we identify the alarmin S100A9 as a novel intracellular antiretroviral factor expressed in human monocyte-derived and skin-derived LC. The intracellular expression of S100A9 is decreased upon LC maturation and inversely correlates with enhanced susceptibility to HIV-1 infection of LC. Furthermore, silencing of S100A9 in primary human LC relieves HIV-1 restriction while ectopic expression of S100A9 in various cell lines promotes intrinsic resistance to both HIV-1 and MLV infection by acting on reverse transcription. Mechanistically, the intracellular expression of S100A9 alters viral capsid uncoating and reverse transcription. S100A9 also shows potent inhibitory effect against HIV-1 and MMLV reverse transcriptase (RTase) activity in vitro in a divalent cation-dependent manner. Our findings uncover an unexpected intracellular function of the human alarmin S100A9 in regulating antiretroviral immunity in Langerhans cells.
| S-EPMC8365256 | biostudies-literature
Project description:Dendritic cells (DC) subsets, like Langerhans cells (LC), are immune cells involved in pathogen sensing. They express specific antimicrobial cellular factors that are able to restrict infection and limit further pathogen transmission. Here, we identify the alarmin S100A9 as a novel intracellular antiretroviral factor expressed in human monocyte-derived and skin-derived LC. The intracellular expression of S100A9 is decreased upon LC maturation and inversely correlates with enhanced susceptibility to HIV-1 infection of LC. Furthermore, silencing of S100A9 in primary human LC relieves HIV-1 restriction while ectopic expression of S100A9 in various cell lines promotes intrinsic resistance to both HIV-1 and MLV infection by acting on reverse transcription. Mechanistically, the intracellular expression of S100A9 alters viral capsid uncoating and reverse transcription. S100A9 also shows potent inhibitory effect against HIV-1 and MMLV reverse transcriptase (RTase) activity in-vitro in a divalent cation dependent manner. Our findings uncover an unexpected intracellular function of the human alarmin S100A9 in regulating antiretroviral immunity in Langerhans cells.
| S-SCDT-EMBOJ-2020-106540 | biostudies-other
Project description:Local restriction of sterile inflammation by auto-inhibitory regulation of S100A8/S100A9-alarmin activity
| PRJNA430869 | ENA
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.
2019-04-08 | GSE109426 | GEO
Project description:Despite advances in our understanding of the underlying genetic abnormalities in myelofibrosis (MF) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly in triple negative MF patients who lack mutations in the JAK2 kinase pathway. Here we report that MYC copy number gain (e.g., trisomy 8) is frequently identified in triple negative MF where MF development and progression rely on MYC-directed activation of S100A9, a Danger Associated Molecular Pattern (DAMP) protein that plays pivotal roles in inflammation. Notably, MYC-S100A9 axis underlies complex network of inflammatory signaling that involves various hematopoietic cell types in the bone marrow microenvironment. Accordingly, small molecules targeting the MYC-S100A9 pathway effectively ameliorated the MF phenotypes, highlighting MYC-alarmin axis as a novel therapeutic vulnerability in a subgroup of MF patients.
2024-04-29 | GSE240963 | GEO
Project description:Prognosis after myocardial infarction (MI) varies greatly depending of the extent of damaged area and the management of biological processes during recovery. Reportedly, the inhibition of the pro-inflammatory S100A9 reduces myocardial damage after MI. We hypothesize that S100A9 blockade induces changes of major signaling pathways implicated in post-MI healing. The S100A9 blocker (ABR-23890) was given for 3 days after coronary ligation. At 3- and 7-days post-MI, ventricle samples were analyzed versus control and sham-operated mice. Blockade of S100A9 modulated the expressed proteins involved in five biological processes: leu-kocyte cell-cell adhesion, regulation of muscle cell apoptotic process, regulation of intrinsic apoptotic signaling pathway, sarcomere organization and cardiac muscle hypertrophy. The blocker induced regulation of 36 proteins interacting with or targeted by the cellular tumor antigen p53, prevented myocardial compensatory hypertrophy, and reduced cardiac markers of post-ischemic stress. The blockade effect was prominent at day 7 post-MI when the quantitative features of ventricle proteome were closer to controls.
2022-05-19 | PXD033683 | Pride
Project description:Alarmins S100A8 and S100A9 are endogenous molecules released in response to environmental triggers and cellular damage. They are constitutively expressed in immune cells such as monocytes and neutrophils and their expression is upregulated under inflammatory conditions. The molecular mechanisms that regulate inflammatory pathways in tendinopathy are largely unknown therefore identifying early immune effectors is essential to understanding the pathology. Based on our previous investigations highlighting tendinopathy as an alarmin mediated pathology we sought evidence of S100A8 & A9 expression in a human model of tendinopathy and thereafter, to explore mechanisms whereby S100 proteins may regulate release of inflammatory mediators and matrix synthesis in human tenocytes. Immunohistochemistry and quantitative RT-PCR showed S100A8 & A9 expression was significantly upregulated in tendinopathic tissue compared with control. Furthermore, treating primary human tenocytes with exogenous S100A8 & A9 significantly increased protein release of IL-6, IL-8, CCL2, CCL20 and CXCL10; however, no alterations in genes associated with matrix remodelling were observed at a transcript level. We propose S100A8 & A9 participate in early pathology by modulating the stromal microenvironment and influencing the inflammatory profile observed in tendinopathy. S100A8 and S100A9 may participate in a positive feedback mechanism involving enhanced leukocyte recruitment and release of pro-inflammatory cytokines from tenocytes that perpetuates the inflammatory response within the tendon in the early stages of disease.
| S-EPMC6365574 | biostudies-literature
Project description:In order to explore how S100A8 and S100A9 may participate in the kidney stone formation, we used recombinant S100A8, recombinant S100A9, or recombinant S100A8/S100A9 heterodimer to culture the HK-2 cells and then sequenced total cellular mRNAS.
2024-11-06 | GSE265848 | GEO
Project description:Recombinant-murine S100A9 were used at 10 mg/50 ml in Hanks Balanced Salt solution (HBSS) or control HBSS administered onto the nares of BALB/C mice. To assess direct effects, mice were sacrificed 1, 4, 6, or 12 h post-inhalation of S100A9. Because S100A9 is reported to initiate proinflammatory responses by ligating TLR4 and/or RAGE, a quantitative PCR array was developed to analyze 49 genes, selected to reflect potential acute inflammatory changes induced by ligation of these receptors. Expression of inflammatory genes was evaluated with the RT-qPCR array. Relative quantities of mRNA in duplicate samples were obtained using the LightCycler® 480 Software 1.5 and the Efficiency-Method.
2016-08-01 | E-GEOD-74128 | biostudies-arrayexpress