Mus musculus
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PROVIDER: PRJNA105703 | ENA |
REPOSITORIES: ENA
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Project description:Myeloid Cell Expressed Proprotein Convertase FURIN Attenuates Inflammation
| PRJNA328082 | ENA
Project description:Furin is a proprotein convertase induced in activated T cells, reported to processes the anti-inflammatory cytokine TGFb-1. Herein, we show that conditional deletion of furin in T cells allowed for normal T cell development but impaired the function of regulatory T cells and effector cells, which produced less TGFb-1. Furin-deficient Treg cells, were less protective in a T cell transfer colitis model and failed to induce Foxp3 in normal T cells. Furin-deficient effector cells were inherently overly active and were resistant to suppressive activity of wild-type Tregs. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its nonredundant, essential function in regulating TGFb-1 production. Targeting furin has emerged as a strategy in malignant and infectious disease. The current work suggests that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance. Experiment Overall Design: Naive CD4+ CD62L+ CD44- T cells were isolated from Fur flox/flox and CD4 cre Fur flox/flox mice. Replicated samples were achieved for wild type and knockout conditions.
2008-10-21 | E-GEOD-11884 | biostudies-arrayexpress
Project description:Furin is a proprotein convertase induced in activated T cells, reported to processes the anti-inflammatory cytokine TGFb-1. Herein, we show that conditional deletion of furin in T cells allowed for normal T cell development but impaired the function of regulatory T cells and effector cells, which produced less TGFb-1. Furin-deficient Treg cells, were less protective in a T cell transfer colitis model and failed to induce Foxp3 in normal T cells. Furin-deficient effector cells were inherently overly active and were resistant to suppressive activity of wild-type Tregs. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its nonredundant, essential function in regulating TGFb-1 production. Targeting furin has emerged as a strategy in malignant and infectious disease. The current work suggests that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance.
2008-06-26 | GSE11884 | GEO
Project description:Analysis of T-cells lacking the proprotein convertase furin. Proprotein convertases promote the proteolytic maturation of proproteins. Furin is induced in activated T-cells. Results provide insight into the function of furin in T-cells.
2015-08-05 | GSE67884 | GEO
Project description:Analysis of T-cells lacking the proprotein convertase furin. Proprotein convertases promote the proteolytic maturation of proproteins. Furin is induced in activated T-cells. Results provide insight into the function of furin in T-cells. CD4+CD62L+CD44- naive, CD4+CD62L-CD44+ memory and CD4+CD25+FoxP3+ regulatory T cells were isolated from Fur flox/flox and CD4 cre Fur flox/flox mice. Naive T cells were activated via TCR. Total RNA was extracted from all cells and hybridized to Affymetrix microarrays.
2015-08-05 | E-GEOD-67884 | biostudies-arrayexpress
Project description:The proprotein convertase enzyme FURIN processes immature pro-proteins into functional end- products. FURIN is upregulated in activated immune cells and it regulates T-cell dependent peripheral tolerance and the Th1/Th2 balance. FURIN also promotes the infectivity of pathogens by activating bacterial toxins and by processing viral proteins. Here, we evaluated the role of FURIN in LysM+ myeloid cells in vivo. Mice with a conditional deletion of FURIN in their myeloid cells (LysMCre-fur(fl/fl)) were healthy and showed unchanged proportions of neutrophils and macrophages. Instead, LysMCre-fur(fl/fl) mice had elevated serum IL-1β levels and reduced numbers of splenocytes. An LPS injection resulted in accelerated mortality, elevated serum pro-inflammatory cytokines and upregulated numbers of pro-inflammatory macrophages. A genome-wide gene expression analysis revealed the overexpression of several pro-inflammatory genes in resting FURIN-deficient macrophages. Moreover, FURIN inhibited Nos2 and promoted the expression of Arg1, which implies that FURIN regulates the M1/M2-type macrophage balance. FURIN was required for the normal production of the bioactive TGF-β1 cytokine, but it inhibited the maturation of the inflammation-provoking TACE and Caspase-1 enzymes. In conclusion, FURIN has an anti-inflammatory function in LysM+ myeloid cells in vivo.
2016-12-30 | GSE84117 | GEO
Project description:ABSTRACT: Furin is a proprotein convertase (PC) responsible for proteolytic activation of a wide array of precursor proteins within the secretory pathway. It maps to the PRC1 locus, a type 2 diabetes susceptibility locus, yet its specific role in pancreatic β cells is largely unknown. The aim of this study was to determine the role of furin in glucose homeostasis. We show that furin is highly expressed in human islets, while PCs that potentially could provide redundancy are expressed at considerably lower levels. β cell-specific furin knockout (βfurKO) mice are glucose intolerant, due to smaller islets with lower insulin content and abnormal dense core secretory granule morphology. RNA expression analysis and differential proteomics on βfurKO islets revealed activation of Activating Transcription Factor 4 (ATF4), which was mediated by mammalian target of rapamycin C1 (mTORC1). βfurKO cells show impaired cleavage of the accessory V-ATPase subunit Ac45, and by blocking this pump in β cells the mTORC1 pathway is activated. Furthermore, βfurKO cells show lack of insulin receptor cleavage and impaired response to insulin. Taken together, these results suggest a model of mTORC1-ATF4 hyperactivation in β cells lacking furin, which causes β cell dysfunction. METHOD: Data obtained for the β cell specific knockout (RIP-Cre+/- furin flox/flox) and control (furin flox/flox) samples were compared to investigate the effect of furin loss on the mRNA profile of islets. Although this method does not directly provide furin targets, the notion of differential gene expression might elucidate affected cellular processes, potentially leading to upstream furin substrates.
2020-05-12 | GSE150312 | GEO
Project description:Absence of the proprotein convertase FURIN in naive and in vitro activated CD8+ T cells
| PRJNA776161 | ENA
Project description:Purpose: FURIN is a member of the proprotein convertase subtilisin/kexin (PCSK) family of serine endoproteases important in converting immature proproteins into their functional form. While FURIN is important in various aspects of the immune response such as in CD4+ T cells, FURIN´s role in CD8+ T cells is unclear. Here, we isolated naive CD8+ T cells from conditional T cell specific Furin KO (Cd4-Cre-Furinflox/flox) and WT (Furinflox/flox) mice and studied the genome-wide gene expression pattern using RNA sequencing. Methods: Total RNA was isolated from the naive CD8+ T cells and the RNA-sequencing data was produced by the Finnish Functional Genomics Centre of Turku Bioscience (University of Turku, Turku, Finland) using Illumina HiSeq 2000. Data processing pipeline was built on Snakemake wrappers, and used STAR to quantify features from quality and adapter trimmed reads in gene level. Prior the normalisation and differential gene expression analysis with DESeq2, the matrix of raw gene counts was prefiltered to keep only rows that have at least 10 reads total. Result tables were annotated with biomaRt. Results: Snakemake preprocessing pipeline measured 55573 genes against GRCm38, ENSEMBL release 97. 15843 of them was used for statistical testing. Full result tables for each treatment were ranked by p-value and the normalized DESeq2 abundances in samples were included. The genes with BH-adjusted p-value <0.05 was considered differentially expressed. Conclusions: Our study revealed that the abscence of FURIN from the naive CD8+ T cells causes an effector-like phenotype in comparison to the WT cells.
2023-04-28 | GSE186812 | GEO
Project description:Purpose: FURIN is a member of the proprotein convertase subtilisin/kexin (PCSK) family of serine endoproteases important in converting immature proproteins into their functional form. While FURIN is important in various aspects of the immune response such as in CD4+ T cells, FURIN´s role in CD8+ T cells is unclear. Here, we isolated naive CD8+ T cells from conditional T cell specific Furin KO (Cd4-Cre-Furinflox/flox) and WT (Furinflox/flox) mice and studied the genome-wide gene expression pattern upon in vitro anti-CD3/anti-CD28 activation (plate-bound, 5µg/ml each) using RNA sequencing. We also used recombinant TGFB1 (0.5ng/ml) or IL12 (10ng/ml) in the same experimental setting to study their impact on the CD8+ T cell transcriptome. Methods: Total RNA was isolated from the stimulated CD8+ T cells and the RNA-sequencing data was produced by the Functional Genomics Unit of the HiLIFE Genome Analysis Infrastructure (University of Helsinki, Helsinki, Finland) using Illumina NextSeq High Output 1x75 bp. Data processing pipeline was built on Snakemake wrappers, and used STAR to quantify features from quality and adapter trimmed reads in gene level. Prior the normalisation and differential gene expression analysis with DESeq2, the matrix of raw gene counts was prefiltered to keep only rows that have at least 10 reads in total. Result tables were annotated with biomaRt. Results: Snakemake preprocessing pipeline measured 55573 genes against GRCm38, ENSEMBL release 97. 17714 of them was used for statistical testing. Full result tables for each treatment were ranked by p-value and the normalized DESeq2 abundances in samples were included. The genes with BH-adjusted p-value <0.05 was considered differentially expressed. Conclusions: Our study revealed that the abscence of FURIN influences the expression of several genes in activated CD8+ T cells. Additionally, although FURIN-deficient CD8+ T cells can respond to exogenous TGFB1 and IL12, administrating these cytokines further increases the number of differentially expressed genes between Furin KO and WT CD8+ T cells.
2023-04-28 | GSE186810 | GEO