Alarmin S100A8/A9 mediates activation of aberrant neutrophils in the pathogenesis of COVID-19
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA664767 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:To characterize the early immune responses against coronavirus infection, we infected rhesus macaques and hACE2 transgenic mice with SARS-CoV-2 and analyzed the transcriptome of infected and non-infected animals. We infected WT mice with IAV as a normal respiratory virus group. During analysis, we found that S100A8 was dramatically upregulated by SARS-CoV-2 and a mouse coronavirus (mouse hepatitis virus, MHV), but not by other tested viruses. A group of non-canonical neutrophils were also activated during SARS-CoV-2 infection.
2021-01-19 | GSE158297 | GEO
Project description:S100A8/A9 is a proinflammatory mediator released by myeloid cells during many acute and chronic inflammatory disorders. However, the precise mechanism of its release from the cytosolic compartment of neutrophils is still elusive. We report here that E-selectin-induced rapid S100A8/A9 release during inflammation occurs in a NLRP3 inflammasome-dependent fashion. Mechanistically, E-selectin engagement triggers Bruton?s tyrosine kinase dependent tyrosine phosphorylation of NLRP3. Concomitant potassium efflux via the voltage-gated potassium channel KV1.3 mediates ASC oligomerization. This is followed by caspase-1 cleavage and downstream activation of pore forming gasdermin D, enabling cytosolic S100A8/A9 to be released. Strikingly, E-selectin-mediated gasdermin D pore formation does not result in cell death, but is a transient process involving activation of the ESCRT-III membrane repair machinery. These findings do not only elucidate the molecular mechanisms of controlled S100A8/A9 release but also identify the NLRP3/gasdermin D axis as a rapid and reversible activation system in neutrophils during inflammation.
2023-10-25 | PXD041652 | Pride
Project description: Not available
| S-EPMC7762710 | biostudies-literature
Project description:Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis. Subconfluent cultures of MC38 cells were serum-starved for 16 hrs and activated with 10ug/mL S100A8/A9 for 6 hrs. Total RNA was extracted from unactivated or activated cells. 2 replicates each per stimulated cells, unstimulated cells, and control cells.
2011-02-01 | E-GEOD-26359 | biostudies-arrayexpress
Project description:Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis.
2011-02-01 | GSE26359 | GEO
Project description:Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease (CVD) and death. The mechanisms linking frailty and cardiovascular outcomes are mostly unknown. Here, we studied the association of abundance (flow cytometry) and gene expression profile (RNAseq) of stem/progenitor cells (HSPCs) and molecular markers of inflammaging (ELISA) with the cardiorespiratory phenotype and prospective adverse events of individuals classified according to levels of frailty. Two cohorts of older adults were enrolled in the study. In a cohort of pre-frail 35 individuals (average age: 75 years), a physical frailty score above the median identified subjects with initial alterations in cardiorespiratory function. RNA sequencing revealed S100A8/A9 upregulation in HSPCs from the bone marrow (>10-fold) and peripheral blood (>200-fold) of individuals with greater physical frailty. Moreover higher frailty was associated with increased alarmins S100A8/A9 and inflammatory cytokines in peripheral blood. We then studied a cohort of 104 more frail individuals (average age: 81 years) with multi-domain health deficits. Reduced levels of circulating HSPCs and increased S100A8/A9 concentrations were independently associated with the frailty index. Remarkably, low HSPCs and high S100A8/A9 simultaneously predicted major adverse cardiovascular events at 1-year follow-up after adjustment for age and frailty index. In conclusion, inflammaging characterized by alarmin and pro-inflammatory cytokines in pre-frail individuals is mirrored by the pauperization of HSPCs in frail older people with comorbidities. S100A8/A9 is upregulated within HSPCs, identifying a phenotype that associates with poor cardiovascular outcomes.
2022-03-23 | GSE190446 | GEO
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
Project description:Tumor recurrence years after seemingly successful treatment of primary tumors is one of the major causes of mortality in cancer patients. Reactivation of dormant tumor cells is largely responsible for this phenomenon. Using models of lung and ovarian cancer, we found a specific mechanism that may govern this process mediated by stress and neutrophils. Stress hormones cause rapid release of S100A8/A9 proteins by neutrophils. S100A8/A9 induce activation of myeloperoxidase resulting in accumulation of oxidized lipids. These lipids up-regulate fibroblast growth factor pathway in tumor cells causing tumor cell exit from the dormancy and formation of tumor lesions. Higher serum levels of S100A8/A9 were associated with shorter time to recurrence in patients with lung cancer after complete tumor resection. Targeting of S100A8/A9 or β2 adrenergic receptors abrogated stress induced reactivation of dormant tumor cells. These observations demonstrate a mechanism linking stress, and specific neutrophils activation with early recurrence in cancer.
2020-11-19 | GSE153944 | GEO
Project description:In an inducible model of human breast cellular transformation, we map genome-wide chromatin binding of S100A8, S100A9 and Pol II. We show that the calcium-dependent cytokines S100A8 and S100A9 are recruited to numerous promoters and enhancers. This recruitment is associated with multiple DNA sequence motifs recognized by DNA-binding transcription factors that are linked to transcriptional activation and are important for transformation. Nuclear-specific expression of S100A8/A9 promotes oncogenic transcription and leads to enhanced breast transformation phenotype. These results suggest that, in addition to its classical cytokine function, S100A8/A9 can act as a transcriptional co-activator.
2021-01-01 | GSE155421 | GEO
Project description:Platelets are central to the pathophysiology of myocardial infarction (MI). How the platelet proteome is altered during MI is unknown. We sought to describe changes in the platelet proteome at the time of MI and identify potential mechanisms. Platelets from patients experiencing ST-elevation myocardial infarction (STEMI) before and 3 days after treatment (n= 30), and a matched cohort of patients with severe stable coronary artery disease (CAD) prior to and 3 days after coronary artery bypass grafting (CABG, n=25) underwent quantitative proteomic analysis. Elevations of the alarmins S100A8 and S100A9 were detected at the time of STEMI compared with stable CAD (S100A8, FC = 2.00, FDR = 0.05; S100A9, FC = 2.28, FDR = 0.005). During STEMI, S100A8 mRNA and protein levels were correlated in platelets (R = 0.46, p = 0.012). To determine if protein synthesis occurs, activated platelets were incubated with 13C-labelled amino acids for 24 hours and analyzed by mass spectrometry. No incorporation was detected, consistent with the notion that protein synthesis in platelets is not a major contributor to the platelet proteome. Platelet abundance of S100A8 and A9 was strongly correlated with neutrophil abundance at the time of STEMI. When isolated platelets and neutrophils were co-incubated under quiescent and TRAP-6 activated conditions, release of S100A8 from neutrophils resulted in uptake of S100A8 by platelets. Leukocyte-to-platelet protein transfer, rather than protein synthesis, may occur in a thromboinflammatory environment such as STEMI, representing a potential new contributor in the innate immune pathogenesis of STEMI.
2023-11-15 | PXD024159 | Pride