TRAIL deletion in myeloid cells augments cholestatic liver injury
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1000508 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25465500_1.fastq.gz | Fastqsanger.gz | |||
| SRR25465500_2.fastq.gz | Fastqsanger.gz | |||
| SRR25465501_1.fastq.gz | Fastqsanger.gz | |||
| SRR25465501_2.fastq.gz | Fastqsanger.gz | |||
| SRR25465502_1.fastq.gz | Fastqsanger.gz |
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Project description:Ductular reactive (DR) cells exacerbate cholestatic liver injury and fibrosis. In this study we posited that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emanating from recruited macrophages restrains DR cell expansion by apoptosis, thereby limiting cholestatic liver injury. Cholestatic liver injury was induced in Wild type (WT), Trailfl/fl and in myeloid-specific Trail deleted (TrailΔmye) C57BL/6 mice using the DDC diet. The DDC diet induced injury and hepatomegaly. However, parameters of liver injury, fibrosis, ductular reaction and inflammation were all increased in the TrailΔmye mice as compared to the WT and Trailfl/fl mice. To better resolve the gene expression profile of cholangiocytes that may promote the recruitment of myeloid cells into the periportal neighborhood, we performed spatial transcriptomics on FPPE liver tissue sections from WT and TrailΔmye mice that were fed the control or DDC diet using the NanoString GeoMx DSP platform (Cat. No. 121401103, GeoMx NGS RNA WTA Mm).
2024-01-31 | GSE239667 | GEO
Project description:Ductular reactive (DR) cells exacerbate cholestatic liver injury and fibrosis. Herein, we posit that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emanates from recruited macrophages and restrains DR cell expansion, thereby limiting cholestatic liver injury. Wild type (WT), Trailfl/fl and myeloid-specific Trail deleted (TrailΔmye) C57BL/6 mice were exposed to DDC diet-induced cholestatic liver injury, which induced hepatomegaly and liver injury as compared to control diet-fed mice. However, parameters of liver injury, fibrosis, and inflammation were all increased in the TrailΔmye mice as compared to the WT and Trailfl/fl mice. High dimensional mass cytometry indicated that cholestasis resulted in increased hepatic recruitment of subsets of macrophages and neutrophils in the TrailΔmye mice. Spatial transcriptomics analysis revealed that the PanCK+ cholangiocytes from TrailΔmye mice had increased expression of the known myeloid attractants S100a8, Cxcl5, Cx3cl1, and Cxcl1. Additionally, in situ hybridization of Cxcl1, a potent neutrophil chemoattractant, demonstrated an increased expression in CK19+ cholangiocytes of TrailΔmye mice. Collectively, these data suggest that TRAIL from myeloid cells, particularly macrophages, restrains a subset of DR cells (i.e., Cxcl1 positive cells), limiting liver inflammation and fibrosis. Reprogramming macrophages to express TRAIL may be salutary in cholestasis.
| S-EPMC10810846 | biostudies-literature
Project description:Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequentlyleads to liver injury, inflammation, fibrosis, and ultimately liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury in α-naphthylisothiocyanate (ANIT)-treated and Mdr2 deficiency mice. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.
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Project description:Liver regeneration after cholestatic damage induced by Rbpj deletion
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Project description:Circulating TRAIL is reduced in cardiovascular disease patients and TRAIL deletion in mice exacerbates disease. The source of TRAIL and protective mechanism(s) are unclear. Monocyte TRAIL mRNA was reduced from coronary artery disease patients, strikingly associating with reduced plasma TRAIL. A strong inverse correlation between plasma TRAIL and IL-18 was observed, with IL-18 repressing monocyte TRAIL mRNA. In mice, two sources were investigated using bone-marrow (BM) transplants; TRAIL expressed only in BM (BM-TRAIL) or everywhere except BM (parenchymal-TRAIL), vs. whole-body TRAIL ablation (null-TRAIL). BM-TRAIL attenuated macrophage content and atherosclerosis. BM-derived macrophages with TRAIL deletion were more inflammatory, with impaired migration and reduced expression of cholesterol efflux, efferocytosis and nitric oxide-controlling genes. TRAIL expression also reduced islet macrophage content, but only parenchymal-TRAIL islets had improved function. Recombinant TRAIL administration stimulated insulin expression and islet mass. We propose TRAIL maintains monocyte/macrophage homeostasis and limits the progression of atherosclerosis and islet dysfunction.
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Project description:Cholestatic injuries, featured with regional damage around the periportal, cause considerable mortality without curative therapies. It is technically challenging to dissect regional cell-cell interactions and molecular changes to fully understand cholangiopathies. Here, we generated a high-definition atlas of spatiotemporal transcriptome during cholestatic injury and repair. Remarkably, cholangiocytes functioned as a periportal hub by integrating signals from neighboring cells. We also dissected periportal damage, spatial heterogenous reprogramming and zonal regeneration, which appeared to be strongly associated with cholangiocyte. Moreover, spatiotemporal analyses revealed a key inhibitory rheostat for hepatocyte proliferation. Together, our study provides a comprehensive resource that is instrumental to demarcate regional cholestatic injury.
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Project description:We used microarrays to provide a transcriptomic signature of different types of cholestasis evoked by 3 different drugs and obstructive surgery Adverse outcome pathways (AOPs) have been recently introduced as tools to map the mechanisms underlying toxic events relevant for chemical risk assessment. AOPs particularly depict the linkage between a molecular initiating event and an adverse outcome through a number of intermediate key events. An AOP has been previously introduced for cholestatic liver injury. The objective of this study was to test the robustness of this AOP for different types of cholestatic insult and the in vitro to in vivo extrapolation. For this purpose, in vitro samples from human hepatoma HepaRG cell cultures were exposed to cholestatic drugs (i.e. intrahepatic cholestasis), while in vivo samples were obtained from livers of cholestatic mice (i.e. extrahepatic cholestasis). The occurrence of cholestasis in vitro was confirmed through analysis of bile transporter functionality and bile acid analysis. Transcriptomic analysis revealed inflammation and oxidative stress as key events in both types of cholestatic liver injury. Major transcriptional differences between intrahepatic and extrahepatic cholestatic liver insults were observed at the level of cell death and metabolism. Novel key events identified by pathway analysis included endoplasmic reticulum stress in intrahepatic cholestasis, and autophagy and necroptosis in both intrahepatic as extrahepatic cholestasis. This study demonstrates that AOPs constitute dynamic tools that should be frequently updated with new input information.
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Project description:To further analyze the change of microRNA (miRNA) between TRAIL-sensitive and TRAIL-resistant Bel-7402 cells Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
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