Platelets orchestrate the resolution of pulmonary inflammation in mice through Treg repositioning and macrophage education
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE171989 | GEO | 2021/04/14
REPOSITORIES: GEO
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Project description:Platelets orchestrate the resolution of pulmonary inflammation in mice through Treg repositioning and macrophage education
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Project description:PDAC cells can activate platelets and change their RNA and protein content, thus, we performed an integrative study investigating the biological processes of differentially spliced mRNAs and expressed miRNAs, as well as proteins. To focus on these “dangerous liaisons”, we used benign disease as a background noise correction for putative inflammatory signals. Gene set enrichment analysis on differential miRNAs, RNA transcripts and proteins revealed an enrichment of RNA splicing, mRNA processing and translation initiation on miRNAs and proteins and depletion on RNA transcripts, as previously described. Furthermore, we provide a new repertoire of PDAC and benign platelet-ome, visualized by the R shiny application, to be exploited for future studies. In conclusion, our data show that platelets change their biological repertoire in the presence of PDAC, through dysregulation of miRNAs and splicing factors, supporting the presence of de novo protein machinery that can “educate” the platelet. This has major clinical implications since the emerging molecules could provide important innovative PDAC biomarkers in the context of liquid biopsies.
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Project description:Platelets are small anucleate cells derived from the fragmentation of megakaryocytes and are involved in different biological processes especially hemostasis, thrombosis and immune response. Platelet purification is a crucial step in transcriptomic analysis, and researchers usually encounter the problem of platelet contamination by leukocytes and erythrocytes. Leukocytes contain much more RNA than platelets, thus the presence of few contaminants in platelet preparation can strongly alter transcriptome results. Using microarray technique, we compared transcriptome of platelets from the same donor, purified by common centrifugation method or using magnetic microbeads to eliminate contaminating cells.
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Project description:Human FOXP3+CD25+CD4+ regulatory T cells (Tregs) play a dominant role in the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. We here performed a high-time-resolution dynamic analysis of the transcriptome during the very early phase of human Treg/ CD4+ T-effector cell activation. After constructing a correlation network specific for Tregs based on these dynamic data, we described a strategy to identify key genes by directly analyzing the constructed undirected correlation network. Six out of the top 10 ranked key hubs are known to be important for Treg function or involved in autoimmune diseases. Surprisingly, PLAU (the plasminogen activator urokinase) was among the 4 new key hubs. We here show that PLAU was critical for expression regulation of FOXP3, EOS and several other important Treg genes and the suppressor function of human Tregs. Moreover, we found Plau inhibits murine Treg development and but promotes the suppressive function. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study shows the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on high-time-resolution data, and highlights a critical role of PLAU in both human and murine Tregs. The construction of a dynamic correlation network of human Tregs provides a useful resource for the understanding of Treg function and human autoimmune diseases. The high-time-resolution time-series transcriptomic data during the very early phase of human Treg/Teff activation could be generally used for further mechanistic analysis of human Treg function. These data could be further used for biological network analysis, dynamic analysis, modeling by experimental researchers, bioinformaticians, computational biologists and systems biologists. We have measured the genome-wide expression of 38,500 genes (probes) by performing a high-time-resolution time-series analysis during the activation process of human regulatory T cells /CD4+ T-effector cells at 19 time points for the first 6h with an equal interval of 20 min. We have also overexpressed the GARP gene in human effector T cells and measured the genome-scale expression for the GARP-overexpressed cells and ThGFP cells at time point 0, 100 and 360min following activation. The stimulation source used in this work is a combination of anti-CD3/-CD28 Dynal beads with IL2 100U/ml.
2012-11-23 | E-GEOD-11292 | biostudies-arrayexpress
Project description:Human blood platelets have important, regulatory functions in diverse hemostatic and pathological disorders, including vascular remodeling, inflammation, and wound repair. Microarray analysis was used to study the molecular basis of essential thrombocythemia, a myeloproliferative disorder with quantitative and qualitative platelet defects associated with cardiovascular and thrombohemorrhagic symptoms, not infrequently neurological. A platelet-expressed gene (HSD17B3) encoding type 3 17beta-hydroxysteroid dehydrogenase (previously characterized as a testis-specific enzyme catalyzing the final step in gonadal synthesis of testosterone) was selectively down-regulated in ET platelets, with reciprocal induction of the type 12 enzyme (HSD17B12). Functional 17beta-HSD3 activity corresponding to approximately 10% of that found in murine testis was demonstrated in normal platelets. The induction of HSD17B12 in ET platelets was unassociated with a concomitant increase in androgen biosynthesis, suggesting distinct functions and/or substrate specificities of the types 3 and 12 enzymes. Application of a molecular assay distinguished ET from normal platelets in 20 consecutive patients (p < 0.0001). These data provide the first evidence that distinct subtypes of steroidogenic 17beta-HSDs are functionally present in human blood platelets, and that the expression patterns of HSD17B3 and HSD17B12 are associated with an uncommon platelet disorder manifest by quantitative and qualitative platelet defects. Keywords: other
2005-11-23 | GSE2006 | GEO
Project description:Gene expression studies comparing IFNg+ Tregs versus IFNg- Tregs from human peripheral blood Ex vivo sorted Tregs (CD25highCD127neg) were stimulated for 4 hours and IFNg-secreting cells were detected by a IFNg-capture kit. The samples were resorted based on IFNg expression.
2016-07-01 | E-GEOD-71274 | biostudies-arrayexpress