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Hematopoietic progenitor cell liabilities and alarmins S100A8/A9 – related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults

ABSTRACT: Hematopoietic progenitor cell liabilities and alarmins S100A8/A9 – related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults

PROVIDER: PRJNA787210 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17168253_1.fastq.gz	Fastqsanger.gz
	SRR17168253_2.fastq.gz	Fastqsanger.gz
	SRR17168254_1.fastq.gz	Fastqsanger.gz
	SRR17168254_2.fastq.gz	Fastqsanger.gz
	SRR17168255_1.fastq.gz	Fastqsanger.gz

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Hematopoietic progenitor cell liabilities and alarmins S100A8/A9 – related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults

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

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

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.

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

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S100A8/A9 promotes dendritic cell-mediated Th17 cell response in SS dry eye

Project description:Sjogren's syndrome (SS) dry eye is a chronic autoimmune eyedisease driven by T helper 17 (Th17)cells. S100A8/A9 has emerged as an important proinflammatory alarmin in variousautoimmune and inflammatory diseases. However, the role of S100A8/A9 in the pathogenesis of SS dry eye remains unexplored. Here,we show that the expression levels of S100A8/A9 were elevated in peripheral blood mononuclear cells (PBMCs) of patients with SS dry eye, as well as the lacrimal glands (LGs) of SS dry eye mice. The administration of paquinimod, a specific inhibitor of S100A8/A9, could alleviate the progression of SS dry eye with significant reduction of Th17 cell frequency in LGs, spleen and lymph nodes of SS dry eye mice.Further experiment revealed that S100A8/A9 did not directly affect Th17 generation and function, but upregulated the expression of MHCIl andI123a in DCs to augment Th17 cell response through a Acod1/STAT3-dependent signaling pathway in the context of SS dry eye. Together,these findings unveiled the key role of S100A8/A9 in the pathogenesis of SS dry eye and suggested a potential therapeutic avenue for SS dry eyeand otherTh7 cell-related autoimmune disorders.

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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.

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E-selectin-mediated rapid NLRP3 inflammasome activation regulates S100A8/A9 release from neutrophils via transient gasdermin D pore formation

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.

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Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy

Project description:Sepsis-induced skeletal muscle atrophy is common in septic patients with the increases risk of mortality and is associated with myocellular mitochondrial dysfunction. Nevertheless, the specific mechanism of sepsis muscle atrophy remains unclear. Here we conducted a clinical retrospective analysis and observed the elevation of skeletal muscle index (ΔSMI) was an independent risk factor for 60-day mortality in septic patients. Moreover, in mouse model of sepsis, the skeletal muscle atrophy was also observed, which was associated with the upregulation of S100a8/a9-mediated mitochondrial dysfunction. Inhibition of S100a8/a9 significantly improved mitochondrial function and alleviated muscle atrophy. Conversely, administration of recombinant S100a8/a9 protein exacerbated mitochondrial energy exhaustion and myocyte atrophy. Mechanistically, S100a8/a9 binding to RAGE induced Drp1 phosphorylation and mitochondrial fragmentation, resulting in muscle atrophy. Additionally, RAGE ablation or administration of Drp1 inhibitor significantly reduced Drp1-mediated mitochondrial fission, improved mitochondrial morphology and function. Our findings indicated the pivotal role of S100a8/a9 in driving the mitochondrial fragmentation in septic muscle atrophy. Targeting S100a8/a9-RAGE-initiated mitochondrial fission might offer a promising therapeutic intervention against septic muscle atrophy. Taken together, our data provide a potential mechanism for sepsis-induced muscle atrophy.

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Hematopoietic progenitor cell liabilities and alarmins S100A8/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults.

Project description:Frailty affects the physical, cognitive, and social domains exposing older adults to an increased risk of cardiovascular disease 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 multidomain 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.

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