S100A8/A9 promotes dendritic cell-mediated Th17 cell response in SS dry eye
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ABSTRACT:
PROVIDER: PRJNA1159115 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30616682_1.fastq.gz | Fastqsanger.gz | |||
| SRR30616682_2.fastq.gz | Fastqsanger.gz | |||
| SRR30616683_1.fastq.gz | Fastqsanger.gz | |||
| SRR30616683_2.fastq.gz | Fastqsanger.gz | |||
| SRR30616684_1.fastq.gz | Fastqsanger.gz |
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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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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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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.
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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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Project description:The graft-versus-host disease (GVHD) associated dry eye disease usually leads to refractory pain and visual impairment with limited treatments currently. Here we found exosome derived from mesenchymal stromal cell (MSC-exo) administered as eye drops significantly alleviates GVHD-associated dry eye disease in human and mouse models. To find out the essential elements during exosome treatment, we performed miRNA sequencing of exosomes derived from MSCs and L929 cells, and identified miR-204 in MSC-exo benefited the recovery of dry eye, which targeted IL-6/IL-6R/Stat3 signaling. Blockade of miR-204 abolished the therapeutic effect of MSC-exo while miR-204 overexpression from L929-exo markedly attenuates dry eye. Thus MSC-exo eye drops are efficacious in treating GVHD-associated dry eye and highlight miR-204 as a potential therapeutic agent.
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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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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.
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Project description:We performed single cell transcriptional profiling of mouse corneal epithelium in a mouse model of dry eye disease.
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Project description:Topical lubrication is the most common remedy for relieving the signs and symptoms of dry eye. However, the therapeutic value of lubricating the ocular surface remains relatively unknown. Here we reveal the restorative properties of the simplest form of lubrication in a mouse model of autoimmune-mediated dry eye. We show topical treatment with PBS rescues corneal stromal architecture through restoring the basement membrane and collagen fiber alignment essential for maintaining corneal transparency. At the single cell level we show keratocytes exhibit significant plasticity under chronic injury, with continuous transition from a homeostatic to inflammatory state, and that lubrication converts these inflammatory cells to a unique reparative phenotype. We further identify IL1b-IL1R1-MAPK signaling as a key pathway driving keratocyte inflammation, and that disruption of the IL1b autocrine amplification loop by lubrication is sufficient to reprogram the inflammatory keratocytes towards the reparative state. Thus, our study underscores the regenerative potential of topical lubrication in dry eye, and reveals fibroblast-targeted therapies as a novel approach to restoring ocular surface health.
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