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WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

ABSTRACT: WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

PROVIDER: PRJNA813315 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18250200_1.fastq.gz	Fastqsanger.gz
	SRR18250200_2.fastq.gz	Fastqsanger.gz
	SRR18250201_1.fastq.gz	Fastqsanger.gz
	SRR18250201_2.fastq.gz	Fastqsanger.gz
	SRR18250202_1.fastq.gz	Fastqsanger.gz

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WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

Project description:Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac remodelling. Recent evidence implicates monocytes/macrophages modulating cardiac fibrosis but targeting these is convoluted, giving their tissue heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis. Here we focus on the role of WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that its myeloid-specific deletion reduces cardiac fibrosis in hypertension-induced NICM. Using the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase driven by Ccl5-expressing Ly6chigh monocytes. Among other cardiac macrophage subtypes, WWP2 dysfunction primarily affects the Ccl5-dependent infiltration and activation of Ly6chigh monocytes, which causes reduced myofibroblast trans-differentiation. WWP2 interacts with IRF7, promoting its non-degradative monoubiquitination, nuclear translocation and transcriptional activity, including upstream Ccl5. Thus, we identify WWP2 as a key regulator of IRF7-mediated Ccl5/Ly6chigh monocyte axis in heart fibrosis.

2022-10-25 | GSE198003 | GEO

The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis.

Project description:Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6chigh monocytes. Among cardiac macrophage subtypes, WWP2 dysfunction primarily affects Ly6chigh monocytes via modulating Ccl5, and consequentially macrophage infiltration and activation, which contributes to reduced myofibroblast trans-differentiation. WWP2 interacts with transcription factor IRF7, promoting its non-degradative mono-ubiquitination, nuclear translocation and transcriptional activity, leading to upregulation of Ccl5 at transcriptional level. We identify a pro-fibrogenic macrophage subtype in non-ischemic cardiomyopathy, and demonstrate that WWP2 is a key regulator of IRF7-mediated Ccl5/Ly6chigh monocyte axis in heart fibrosis.

| S-EPMC9712659 | biostudies-literature

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Project description:Bulk RNA-seq heart left ventricle data from wild type and WWP2 gene mutant mice (after 28 days of angiotensinII treatment)

2019-07-08 | GSE130468 | GEO

TaqMan mouse miRNA array profile of LY6CHigh and LY6Clow monocyte

Project description:TaqMan mouse miRNA array profile of LY6CHigh and LY6Clow monocyte

| PRJNA566405 | ENA

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [ChIP-Seq]

Project description:Renal fibrosis is a common pathological endpoint that is challenging to reverse in chronic kidney disease (CKD) independently of the underlying causes. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM), recent reports revealed their heterogeneity in proliferative and fibrotic activities, mirroring specific metabolic states that drive fibrosis. Here, we investigate the role of E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of renal myofibroblasts in fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients and in pre-clinical models of CKD. WWP2 deficiency leads to increased fatty acid oxidation, boosting mitochondrial respiration, promoting myofibroblast proliferation and arresting pro-fibrotic activation, thus ameliorating kidney fibrosis. Specifically, WWP2 suppresses the transcription of PGC-1α, which mediates the metabolic and proliferative changes in fibrotic myofibroblasts. Pharmacological intervention targeting PGC-1α reverses the pro-fibrotic effect of WWP2. These findings reveal a previously unappreciated WWP2-PGC-1α axis underlying the metabolic reprogramming of myofibroblasts during renal fibrosis, which could provide a new target for therapeutic intervention in CKD.

2024-05-19 | GSE267765 | GEO

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [scRNA-seq]

2024-02-05 | GSE241502 | GEO

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS [bulk RNA-seq]

2024-02-05 | GSE241503 | GEO

Identification of miR-146a target genes in mouse monocyte subsets

Project description:To gain insight into the mechanisms underlying miR-146a-mediated modulation of Ly6Chigh monocyte function, we compared the expression profiles of Ly6Chigh and Ly6Clow monocytes in miR-146a+/+ (WT) versus miR-146a-/- (KO) conditions.

2019-06-01 | GSE77159 | GEO

Single cell RNA seq reveals cellular and transcriptional heterogeneity in the splenic CD11b+Ly6Chigh monocyte population expanded in sepsis-surviving mice

Project description:Patients surviving a septic episode exhibit persistent immune impairment and increased mortality due to enhanced infection vulnerability. In the present study, using the cecal ligation and puncture (CLP) model of polymicrobial sepsis, we addressed the hypothesis that functional, metabolic, and phenotypic alterations in splenic CD11b+Ly6Chigh myeloid cells contribute to the immune impairment in sepsis-surviving mice. Herein, we showed the cellular and transcriptional heterogeneity of the expanded splenic CD11b+Ly6Chigh population in CLP-survivors. We also showed that CD11b+Ly6Chigh cells presented phenotypic and functional disparity between C57BL6/J and BALB/c strains.

2024-11-13 | GSE249839 | GEO

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Project description:WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

| PRJNA540306 | ENA