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CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE199640 | GEO | 2023/10/02

REPOSITORIES: GEO

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CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [bulk RNA-seq]

Project description:Obesity is increasing worldwide and leads to a multitude of metabolic diseases including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatosis (NASH). Here we examine the role of CYR61 in liver fibrosis and inflammation and its potential as a therapeutic target. Loss of CYR61 during NASH injury improves glucose tolerance, decreases liver inflammation and reduces fibrosis. CYR61 activates signaling in monocytes and monocyte-derived macrophages promoting a pro-inflammatory/pro-fibrotic phenotype through a CYR61/SYK/NFKB signaling cascade. In vitro, CYR61 activates Pdgfa and Pdgfb expression in macrophages in a NFκB-dependent manner. Ultimately, we identify a potential therapeutic for NASH: a CYR61-blocking antibody that reduces fibrotic injury and CYR61-driven signaling in macrophages in vitro and in vivo. This study demonstrates that CYR61 is a key driver of liver inflammation and fibrosis and a strong therapeutic target for treatment of NAFLD/NASH.

2023-10-02 | GSE199637 | GEO

CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [HIVE single-cell RNA-seq]

2023-10-02 | GSE199639 | GEO

CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [10X single-cell RNA-seq]

2023-10-02 | GSE199638 | GEO

CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages

Project description:CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages

| PRJNA820904 | ENA

CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [bulk RNA-seq]

Project description:CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [bulk RNA-seq]

| PRJNA820908 | ENA

CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [10X single-cell RNA-seq]

Project description:CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [10X single-cell RNA-seq]

| PRJNA820907 | ENA

CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [HIVE single-cell RNA-seq]

Project description:CYR61 orchestrates NASH fibrosis through SYK-NFκB-PDGF signaling in monocyte-derived macrophages [HIVE single-cell RNA-seq]

| PRJNA820906 | ENA

Targeting SYK of monocyte-derived macrophages regulates liver fibrosis via crosstalking with Erk/Hif1α and remodeling liver inflammatory environment.

Project description:Liver fibrosis is a danger signal indicating a huge risk of liver cancer occurrence, but there is still no effective clinical means to regulate the progress of liver fibrosis. Although a variety of drugs targeting SYK have been developed for tumors and autoimmune diseases, the mechanism and specific efficacy of SYK's role in liver fibrosis are not yet clear. Our studies based on chronic CCL4, bile duct ligation, and subacute TAA mouse models show that SYK in monocyte-derived macrophages (MoMFs) is fully dependent on phosphorylation of Erk to up-regulate the expression of Hif1α, thereby forming the crosstalk with SYK to drive liver fibrosis progress. We have evaluated the ability of the small molecule SYK inhibitor GS9973 in a variety of models. Contrary to previous impressions, high-frequency administration of GS9973 will aggravate CCL4-induced liver fibrosis, which is especially unsuitable for patients with cholestasis whose clinical features are bile duct obstruction. In addition, we found that inhibition of MoMFs SYK impairs the expression of CXCL1, on one hand, it reduces the recruitment of CD11bhiLy6Chi inflammatory cells, and on the other hand, it promotes the phenotype cross-dress process of pro-resolution MoMFs, thereby remodeling the chronic inflammatory environment of the fibrotic liver. Our further findings indicate that on the basis of the administration of CCR2/CCR5 dual inhibitor Cenicriviroc, further inhibiting MoMFs SYK may give patients with fibrosis additional benefits.

| S-EPMC8636632 | biostudies-literature

A vasculature niche orchestrates stromal cell phenotype through PDGF signaling: Importance in human fibrotic disease.

Project description:SignificanceTissue fibrotic diseases, for example of the liver and lung, represent a huge unmet medical need. In this study, using single-cell RNA sequencing, cytometry by time of flight (CyTOF), tissue imaging, and functional assays, we identify a complex vascular niche in Dupuytren's disease (DD), a common localized fibrotic condition of the palm, where early-disease-stage tissue can be accessed readily. We uncover a population of myofibroblast precursors within the pericyte compartment and demonstrate that the endothelium instructs the differentiation of functionally distinct stromal cells, thereby orchestrating discrete microenvironments in the fibrotic milieu. Together, these findings provide a basis for the concept of targeting blood vessel signaling to control the progression of human fibrosis.

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Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH.

Project description:Accumulation of lipotoxic lipids, such as free cholesterol, induces hepatocyte death and subsequent inflammation and fibrosis in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. β-cyclodextrin polyrotaxane (βCD-PRX), a unique supramolecule, is designed to elicit free cholesterol from lysosomes. Treatment with βCD-PRX ameliorated cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals, thereby suppressing liver fibrosis in a NASH model, without affecting the hepatic cholesterol levels. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.

| S-EPMC10506914 | biostudies-literature

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