Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE198003 | GEO | 2022/10/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

Project description:WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis

| PRJNA813315 | ENA

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

2024-02-05 | GSE241502 | GEO

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

2024-05-19 | GSE267765 | GEO

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

2024-02-05 | GSE241503 | GEO

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

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

| PRJNA540306 | ENA

Triggering of NOD2 receptor converts inflammatory Ly6Chigh into Ly6Clow monocytes with patrolling properties.

Project description:In the present study, we demonstrate that NOD2 receptor triggering by muramyl dipeptide converts blood inflammatory Ly6Chigh monocytes into patrolling Ly6Clow monocytes. Muramyl dipeptide administration to Nr4a1-/- mice, which lack Ly6Clow monocytes, and to Ly6Clow-depleted mice leads to the emergence of blood patrolling monocytes expressing phenotypic profile of typical Ly6Clow monocytes, including high expression of CX3CR1 and LFA1. Furthermore using intravital microscopy in live animal models of inflammatory diseases, we observed that converted Ly6Chigh monocytes are capable of patrolling the endothelium of blood vessels and their presence contributes to reduce the inflammatory response following muramyl dipeptide injection.

2019-01-14 | GSE101496 | GEO

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

WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS

Project description:WWP2 MEDIATES THE METABOLIC REPROGRAMMING OF RENAL MYOFIBROBLASTS TO PROMOTE KIDNEY FIBROSIS

| PRJNA1008450 | ENA

Enzymatic Analysis of WWP2 E3 Ubiquitin Ligase Using Protein Microarrays Identifies Autophagy-Related Substrates

Project description:WWP2 is a HECT E3 ligase that targets protein Lys residues for ubiquitination. As a member of the NEDD4 family of E3 ligases, WWP2 is comprised of an N-terminal C2 domain, four central WW domains, and a C-terminal catalytic HECT domain. The peptide segment between the middle WW domains, the 2,3-linker, can autoinhibit the catalytic domain and this can be relieved by phosphorylation at Tyr369. Several protein substrates of WWP2 have been identified, including the tumor suppressor lipid phosphatase PTEN, but the full substrate landscape and biological functions of WWP2 remain to be elucidated. Here we use protein microarray technology and the activated enzyme phosphomimetic mutant WWP2Y369E to identify potential WWP2 substrates. We identified 31 substrate hits for WWP2Y369E using protein microarrays of which three are the autophagy receptors, NDP52, OPTN, and SQSTM1. These three hits were validated with in vitro and cell-based transfection assays and the Lys ubiquitination sites on these proteins were mapped by mass spectrometry. Among the mapped ubiquitin sites on these autophagy receptors, many were previously identified in studies on the endogenous proteins. WWP2 knockout SH-SH5Y neuroblastoma cells using CRISPR-Cas9 showed a defect in mitophagy in a fashion that could be rescued by WWP2Y369E transfection. These studies suggest that WWP2-mediated ubiquitination of the autophagy receptors NDP52, OPTN, and SQSTM1 may positively contribute to the regulation of autophagy.

2022-05-20 | PXD031703 | Pride

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data