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Effect of blocking A2aR in sepsis on the Treg transcriptome

ABSTRACT: In our study, blocking A2aR with ZM241385 was found to inhibit Foxp3 expression in Treg cells of septic mice. Therefore, we used flow cytometry to sort mouse spleen CD4+CD25+ cells for transcriptome sequencing in an attempt to discover the mechanism by which blocking A2aR affects Foxp3 expression. The specific groupings were as follows: naive groups (N1-N5), CLP groups (C1-C5), CLP+A2aR antagonist groups (Z1-Z6).

ORGANISM(S): Mus musculus

PROVIDER: GSE244227 | GEO | 2023/10/03

REPOSITORIES: GEO

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Project description:Dysregulated cardiac function after sepsis is common in intensive care unit (ICU) and known to predict poor long-term outcome and increase mortality. Effective therapeutic strategies are largely lacking. Moreover, the pathological feature and the molecular mechanism underlying cardiac dysfunction induced by sepsis remain unclear. Here, by performing echocardiograms on rodents after induction of polymicrobial sepsis with cecum ligation and puncture (CLP), we assessed the temporal dynamics of left ventricular ejection fraction (LVEF) and a serial of hemodynamics parameters on animals at different time point after CLP. Intriguingly, the mean LVEF is comparable in mice induced by CLP and sham, whereas survivors post CLP had stable LVEF and non-survivors had markedly fluctuated LVEF at early phase of CLP induction, suggesting LVEF away from normal range is highly associated with mortality. Consistent with clinical observations of depressed, preserved or hyperdynamic LVEF in septic patients from data compiled using our ICU cohort and from other studies, CLP-induced mice fall into three groups based on LVEF measured at 24 hours after surgery: high LVEF (HEF, LVEF>=90%), low LVEF (LEF, LVEF<65%), and normal LVEF (NEF, 65%=<LVEF<90%). We performed genome-wide transcriptomic and proteomic profiling on left ventricle samples collected from three CLP groups and sham mice. By implementing pathway analysis, gene set enrichment and coexpression network analysis, we identified jointly and distinctively changed genes, proteins and biologically-essential processes and pathways in three CLP groups with different LVEF. Notably, transmission electron microscopy examination shows remarkable mitochondrial and sarcomere defects in three CLP groups with different phenotypes associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury, serving as a framework for future research into pathology and molecular mechanism of sepsis-induced cardiomyopathy.

Project description:The Caenorhabditis elegans somatic gonad was the first organ to have its cell lineage determined, and the gonadal lineages of the two sexes differ greatly in their pattern of cell divisions, cell migration and cell types. Despite much study, the genetic pathways that direct early gonadal development and establish its sexual dimorphism remain largely unknown, with just a handful of regulatory genes identified from genetic screens. To help define the genetic networks that regulate gonadal development, we employed cell-specific RNA-seq. We identified transcripts present in Z1/Z4 or Z1/Z4 daughter cells in each sex at the onset of somatic gonadal sexual differentiation. For comparison, transcripts were identified in whole animals at both time points. Pairwise comparisons of samples identified several hundred gonad-enriched transcripts, including most known Z1/Z4-enriched mRNAs, and reporter analysis confirmed the effectiveness of this approach. Prior to the Z1/Z4 division few sex-biased Z1/Z4 transcripts were detectable, but less than six hours later, we identified more than 250 sex-biased transcripts in the Z1/Z4 daughters, of which about a third were enriched in the somatic gonad cells compared to cells from whole animals. This indicates that a robust sex-biased developmental program, some of it gonad-specific, initiates in these cells around the time of the first Z1/Z4 division. Cell-specific analysis also identified approximately 70 previously unannotated mRNA isoforms that are enriched in Z1/Z4 or their daughters. Our data suggest that early sex differentiation in the gonad is controlled by a relatively small suite of differentially expressed genes, even after dimorphism has become apparent. 20 total sample: two time points, two sexes, and gonadal cells or whole animals. The earlier time point was collected in triplicate and was harvested 9.5 hours after starved, hatched L1s were fed. The later time point was collected in duplicate and was harvested 15 hour after starved, hatched L1 were fed. Replicates of either dissociated whole animals or gonadal cells (Z1/Z4 or Z1/Z4 daughter) from both male and hermaphrodites were harvested for each time point.

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Effect of blocking A2aR in sepsis on the Treg transcriptome

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