NFAT signalling in human mesenchymal stromal cells affects extracellular matrix metabolism and anti-fungal immune responses
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA663579 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12643306.fastq.gz | Fastqsanger.gz | |||
| SRR12643307.fastq.gz | Fastqsanger.gz | |||
| SRR12643308.fastq.gz | Fastqsanger.gz | |||
| SRR12643309.fastq.gz | Fastqsanger.gz | |||
| SRR12643310.fastq.gz | Fastqsanger.gz |
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Project description:Mesenchymal stromal cells (MSCs) combined with calcineurin-NFAT (CN-NFAT) inhibitors are being tested as a treatment for graft versus host disease (GvHD). The immunosuppressive properties of MSCs seem beneficial; however, their response during fungal infection, which is an important cause of mortality in GvHD patients, is unknown. We report that MSCs phagocytose the fungal component zymosan, resulting in phosphorylation of Syk kinase, increase in cytosolic calcium levels and ultimately, in NFAT1 nuclear translocation. RNA-sequencing analysis of zymosan-treated MSCs showed that CN-NFAT inhibition affects extracellular matrix (ECM) genes, but not cytokine expression that is under the control of the NF-κB pathway. When co-culturing MSCs or decellularized MSC-ECM with human peripheral blood mononuclear cells (PBMCs), selective NFAT inhibition in MSCs decreased cytokine expression by PBMCs. These findings reveal a dual mechanism underlying the MSC response to zymosan: while NF-κB directly controls inflammatory cytokine expression, NFAT impacts immune-cell functions by regulating ECM remodelling.
2021-06-14 | GSE157981 | GEO
Project description:The nephrotoxic ifosfamide-metabolite chloroacetaldehyde (CAA) induces changes in intracellular Ca2+-concentration of human RPTEC. This effect is due to a PKA-dependent inhibition of Na+/Ca2+ exchange (Benesic, A., Schwerdt, G. at. al. (2005) Kidney Int 68, 2029-2041). Thus, possible effects of CAA-exposure on cAMP and Ca2+ regulated genes as well the Ca2+/NFAT pathway were investigated by cDNA-microarray analysis. Both microarrays (cAMP/Ca2+ and Ca2+(NFAT) were performed twice. After 24 h CAA exposure a marked downregulation of c-fos and junB was observed in all arrays performed. In the cAMP/Ca2+-arrays downregulation of FOS, ADRB1, INHBA, CDK5, IL2, PLN, SRF, GCG, SGK, JUNB, BDNF, S100A6, CCNA1, MIF, HK2, SST and EGR2 by CAA was observed in two independent experiments. From the AP-1 family expression of junD and fosB were not altered. Overexpression by CAA of CREB and DDIT3 were only observed in one of two experiments. JUND, FOSB, FOSL1, CREM and CREBBP expression was not influenced in reproducible manner, as well as all members of the NFAT-family. In the Ca2+/NFAT-Arrays, PPP3CB, VAV3, NFATC1, IL8, IL6, FASLG, IL3, IFNB1, FOS, BCL2, EGR3, CD3G, HRAS, EP300, IL4, CALM3, RELA, EGR2, NPPB, IFNG, NFATC4, KPNA5, CAMK2BNFKB2 , VEGF, IL8RA, IL2,GATA4, MEF2A, PTPRC, ICOS, NFKBIE, CDKN1A, CSNK2B, ACTB, MEF2B and JUNB mRNA´s were repeatedly reduced by CAA exposure. The only gene with upregulation in both experiments was found to be IFN-alpha. Thus CAA exposure for 24 h leads to a downregulation of of the AP-1 members JUNB and FOS, whereas there is small positive effect on CREB mRNA. CAA reproducibly lowers the expression of IL-2, 3, 4, 6 and 8, whereas the levels of TNFalpha and TGFbeta1 and 3 mRNA were not altered. IFN-alpha mRNA levels were reproducibly increased (>2-fold). In conclusion, CAA seems to interact with Ca2+ and cAMP signalling pathways, with a strong impact on AP-1 proteins and inflammatory signalling. Keywords: stress response to toxic agent
2006-06-30 | GSE4956 | GEO
Project description:Calcineurin-nuclear factor of activated T-cell (CN-NFAT) inhibitors are widely clinically used drugs for immunosuppression but besides their required T-cell response inhibition, they also undesirably affect innate immune cells. Disruption of innate immune cell function can explain the observed susceptibility of CN-NFAT inhibitors-treated patients to opportunistic fungal infections. Neutrophils play a crucial role in the innate immunity pathogen defense, while however the effect of CN-NFAT inhibitors on neutrophil function is poorly described. Thus, we tested the response of human neutrophils to fungal pathogens, namely Candida albicans and Aspergillus fumigatus in the presence of CN-NFAT inhibitors. We report that the NFAT pathway members are expressed in neutrophils and mediates part of the neutrophil response to pathogens. Upon pathogen exposure, neutrophils underwent profound transcriptomic changes. Importantly, genes involved in the regulation of the immune response and chemotaxis, including the chemokines CCL2 , CCL3, and CCL4 were significantly upregulated. The presence of CN-NFAT inhibitors attenuated the expression of these chemokines and impaired the ability of neutrophils to chemoattract other immune cells. Our results amend knowledge about the impact of CN-NFAT inhibition in human neutrophils.
2024-05-21 | GSE259282 | GEO
Project description:Mesenchymal stromal cells (MSCs) combined with calcineurin-nuclear factor of activated T cell (CN-NFAT) inhibitors are being tested as a treatment for graft-versus-host disease (GvHD). The immunosuppressive properties of MSCs seem beneficial; however, their response during fungal infection, which is an important cause of mortality in patients with GvHD , is unknown. We report that MSCs phagocytose the fungal component zymosan, resulting in phosphorylation of spleen tyrosine kinase (Syk), increase in cytosolic calcium levels, and ultimately, increase in NFAT1 nuclear translocation. RNA sequencing analysis of zymosan-treated MSCs showed that CN-NFAT inhibition affects extracellular matrix (ECM) genes but not cytokine expression that is under the control of the NF-κB pathway. When coculturing MSCs or decellularized MSC-ECM with human peripheral blood mononuclear cells (PBMCs), selective NFAT inhibition in MSCs decreased cytokine expression by PBMCs. These findings reveal a dual mechanism underlying the MSC response to zymosan: while NF-κB directly controls inflammatory cytokine expression, NFAT impacts immune-cell functions by regulating ECM remodeling.
| S-EPMC8233198 | biostudies-literature
Project description:CRELD2 is a novel modulator of calcium mobilisation and calcineurin-NFAT signalling during osteoclast differentiation
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Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A. bone marrow cells from C57B/6 mice were stimulated in Flt3-L suplemented media in presence or absence of calcineurin/NFAT inhibitor Cyclosporin A, samples in 3 biological replicates
2011-09-30 | E-GEOD-29094 | biostudies-arrayexpress
Project description:Nuclear factor of activated T cells (NFAT) comprises a family of transcription factors that regulate T cell development, activation and differentiation. NFAT signaling can also mediate granulocyte and DC activation, but it is unknown whether NFAT influences their development from progenitors. Here we report a novel role for calcineurin/NFAT signaling as a negative regulator of myeloid hematopoiesis. Reconstituting lethally-irradiated mice with hematopoietic stem cells expressing an NFAT-inhibitory peptide resulted in enhanced development of the myeloid compartment. Culturing bone marrow cells with Flt3-L and Cyclosporin A, which inhibits NFAT signaling, increased numbers of differentiated DC. Global gene expression analysis of untreated DC and NFAT-inhibited DC revealed differential expression of transcripts that regulate cell cycle and apoptosis. Thus, calcineurin/NFAT signaling negatively regulates myeloid lineage development. The finding that NFAT acts as a negative regulator of myeloid development provides novel insight in understanding immune responses during treatment with calcineurin/NFAT inhibitors as Cyclosporin A.
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Project description:Decellularized Spinal Cord Matrix Manipulate Glial Niche Alteration via Serglycin Mediated Signalling Pathway
| PRJNA837176 | ENA
Project description:Alternative splicing is a potent modifier of protein function. Stromal interaction molecule 1 (Stim1) is the essential activator of store-operated Ca2+ entry (SOCE) triggering activation of transcription factors. Here, we characterize Stim1A, a splice variant with an additional 31 amino acid domain inserted in frame within its cytosolic domain. Prominent expression of exon A is found in astrocytes, heart, kidney and testes. Full length Stim1A functions as a dominant-negative regulator of SOCE and ICRAC, facilitating sequence specific fast calcium dependent inactivation and destabilizing gating or Orai1. Downregulation or absence of native Stim1A results in increased SOCE. Despite reducing SOCE, Stim1A leads to increased NFAT translocation. Differential proteomics revealed interference of Stim1A with the cAMP-SOCE crosstalk by altered modulation of phosphodiesterase (PDE8B), resulting in reduced cAMP degradation and increased PIP5K activity, facilitating an increased NFAT activation. Our study uncovers a hitherto unknown mechanism regulating NFAT activation and indicates that cell type specific splicing of Stim1 is a potent means to regulate the NFAT signalosome and cAMP-SOCE crosstalk.
2021-11-11 | PXD028974 | Pride
Project description:Diffuse large B-cell lymphoma (DLBCL) represents the most common form of lymphoma. We could show that in DLBCL cell lines the transcription factor NFAT is constitutively activated and drives the survival of a DLBCL subset. Aim of the analysis was to identify NFAT target genes in a NFAT-dependent (HBL-1) or -independent (HT) DLBCL cell line. To block NFAT activity, the DLBCL cells were treated with the calcineurin inhibitor cyclosporin A (CsA) up to 48 h. With this approach, we identified several survival-related NFAT target genes in HBL-1 cells that might explain the toxic effects of calcineurin inhibitors.
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