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A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: effect of CLP/SHAM in Hnf4a WT and KO mice

ABSTRACT: A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: effect of CLP/SHAM in Hnf4a WT and KO mice

PROVIDER: PRJNA1082376 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28171249.fastq.gz	Fastqsanger.gz
	SRR28171250.fastq.gz	Fastqsanger.gz
	SRR28171251.fastq.gz	Fastqsanger.gz
	SRR28171252.fastq.gz	Fastqsanger.gz
	SRR28171253.fastq.gz	Fastqsanger.gz

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Project description:Sepsis is a life-threatening condition with multi-organ failure caused by a dysregulated host response to infection. Among different organs susceptible to infection, the lung is the main one leading to sepsis 4. Patients with severe sepsis are at a high risk of developing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which occurs in up to 50% of patients. Myeloid C-type lectin domain family 5 member A (CLEC5A) is a pattern recognition receptor that participates in host defense against infection. Blockage of CLEC5A increased survival of mice with polymicrobial sepsis or endotoxemia, and protected the lungs against septic infection. To explore the underlying cellular and molecular mechanisms of CLEC5A in sepsis-induced lung injury, a comprehensive single-cell transcriptomics of CLEC5A-/- lungs was generated by scRNA-seq. Mice were subjected to cecal ligation and puncture (CLP), and the lungs were collected 12 h post-surgery. Single cell suspensions were prepared from lung tissues of three CLEC5A-/- mice and three WT littermates, and pooled cells from these mice were subjected to scRNA-seq processing using the 10×Genomics Chromium system. A total of 55,177 single cells, including 29,306 cells from WT lungs and 15,871 cells from CLEC5A-/- lungs, were obtained after removal of multiplets and filtration of low-quality cells. Total cells were grouped into 34 distinct clusters by Uniform Manifold Approximation and Projection, and a total of 14 distinct cell types were identified, including granulocytes, T cells, B cells, alveolar-macrophages (AM), monocytes, macrophages, natural killer T cells (NKT), mesothelium, natural killer cells (NK), endothelial cells, fibroblasts, dendritic cells (DC), epithelial cells, and smooth muscle cells (SMC).The scRNA-seq analysis implied the potential role of CLEC5A in endothelial cells regarding crosstalk with immune cells in septic lungs. Deletion of CLEC5A inhibited endothelial barrier dysfunction induced by sepsis, and decreased leukocyte-endothelial adhesion and transendothelial migration. The role of CLEC5A in pulmonary endothelial cells and the barrier function is identified for the first time, which contributes to the regulation of immunity/inflammation in the lungs under septic infection. This work extends the therapeutic potential of targeting CLEC5A in sepsis-induced endothelial barrier dysfunction and lung injury.

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.

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A critical role for Hepatocyte Nuclear Factor 4 alpha in polymicrobial sepsis-associated metabolic reprogramming and death: effect of CLP/SHAM in Hnf4a WT and KO mice

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