COMMD10-deficiency in adipose tissue macrophages attenuates obesity and insulin resistance by boosting mitochondrial and antioxidant functions
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ABSTRACT:
PROVIDER: PRJNA1037136 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26729728_1.fastq.gz | Fastqsanger.gz | |||
| SRR26729728_2.fastq.gz | Fastqsanger.gz | |||
| SRR26729729_1.fastq.gz | Fastqsanger.gz | |||
| SRR26729729_2.fastq.gz | Fastqsanger.gz | |||
| SRR26729730_1.fastq.gz | Fastqsanger.gz |
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Project description:During obesity, adipose tissue macrophages (ATM) colonize the white adipose tissue (WAT), where they adapt inflammatory and metabolically activated phenotypes. Here, we demonstrate that COMMD10 is a key regulator of macrophage oxidative capacity in response to chronic caloric excess. Mice with COMMD10-deficiency targeted to macrophages were fed with high-fat-diet (HFD) for 12 weeks. They gained less weight despite similar food intake, and showed improved systemic metabolic indices, sustained adipose tissue insulin sensitivity, increased lipolysis and reduced adipocyte hypertrophy and liver steatosis. COMMD10-deficient ATM directly improved insulin sensitivity and increase lipolysis in co-cultured adipocytes. COMMD10-deficient ATM exhibited increased oxidative respiration and mitochondrial membrane potential after short term (five weeks) and chronic (12 weeks) HFD. Their oxidative respiration was fueled by both glucose and lipids. They better adapted to mitochondrial activation by upregulating NRF2-dependent antioxidant transcriptional module. their increase in mitochondrial activity was furthered supported by COMMD10 modulation of cellular copper-iron balance and interaction with various oxidative phosphorylation related proteins. Our study illuminates COMMD10 as a pivotal regulator of mitochondrial energy production in ATM during constant energy surplus.
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Project description:To evaluate whether NAD+-boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts IFNg and IL-17 secretion with greater effects on TH17 polarization. RNA-seq analysis implicates NR blunting of sequestosome 1 (SQSTM1/p62)-coupled oxidative stress. NR administration increases SQSTM1 and reduces reactive oxygen species (ROS) levels. Furthermore NR activates NRF2, and genetic knockdown of NRF2 and of the NRF2-dependent gene, SQSTM1 diminish NR amelioratory effects. Metabolomic analysis identify that NAD+-boosting increases arginine and fumarate biosynthesis and genetic knockdown of argininosuccinate lyase ameliorates NR-effects on IL-17 production. Hence, NR via amino acid metabolites orchestrate NRF2 activation, augments CD4+ T cell antioxidant defenses and attenuates TH17 responsiveness. Oral NR supplementation in healthy volunteers similarly increase serum arginine, SQSTM1 and antioxidant enzyme gene expression and blunts TH17 immune responsiveness, supporting evaluation of NAD+-boosting in CD4+ T cell linked inflammation.
2023-07-18 | GSE237555 | GEO
Project description:To evaluate whether NAD+-boosting modulates adaptive immunity, primary CD4+ T cells from healthy control and psoriasis subjects were exposed to vehicle or nicotinamide riboside (NR) supplementation. NR blunts IFNg and IL-17 secretion with greater effects on TH17 polarization. RNA-seq analysis implicates NR blunting of sequestosome 1 (SQSTM1/p62)-coupled oxidative stress. NR administration increases SQSTM1 and reduces reactive oxygen species (ROS) levels. Furthermore NR activates NRF2, and genetic knockdown of NRF2 and of the NRF2-dependent gene, SQSTM1 diminish NR amelioratory effects. Metabolomic analysis identify that NAD+-boosting increases arginine and fumarate biosynthesis and genetic knockdown of argininosuccinate lyase ameliorates NR-effects on IL-17 production. Hence, NR via amino acid metabolites orchestrate NRF2 activation, augments CD4+ T cell antioxidant defenses and attenuates TH17 responsiveness. Oral NR supplementation in healthy volunteers similarly increase serum arginine, SQSTM1 and antioxidant enzyme gene expression and blunts TH17 immune responsiveness, supporting evaluation of NAD+-boosting in CD4+ T cell linked inflammation.
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Project description:The COMMD (Copper metabolism MURR1 domain containing) family includes ten structurally conserved proteins (COMMD1 to COMMD10) in eukaryotic multicellular organisms which are involved in a diverse array of cellular and physiological processes, including endosomal trafficking, copper homeostasis, and cholesterol metabolism, among others. To understand the role of COMMD10 in embryonic development, we used Commd10Tg(Vav1-icre)A2Kio/J mice, where the Vav1-cre transgene is integrated into an intron of the Commd10 gene, creating a functional knockout of Commd10 in homozygous mice. Breeding of heterozygous mice produced no COMMD10-deficient (Commd10Null) offspring, suggesting that COMMD10 is required for embryogenesis. Analysis of Commd10Null embryos demonstrated that they display stalled development by embryonic day 8.5 (E8.5). Transcriptome analysis revealed that numerous neural crest-specific gene markers had lower expression in mutant versus wild-type (WT) embryos. Specifically, Commd10Null embryos displayed significantly lower expression levels of a number of transcription factors, including a major regulator of the neural crest, Sox10. Moreover, several cytokines/growth factors involved in early embryonic neurogenesis were also lower in mutant embryos. On the other hand, Commd10Null embryos demonstrated higher expression of genes involved in tissue remodeling and regression processes. Taken together, our findings show that Commd10Null embryos die by day E8.5 due to COMMD10-dependent neural crest failure, revealing a new and critical role of COMMD10 in neural development.
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Project description:Most tissue-resident macrophages are established prenatally and self-maintain independently of bone marrow (BM) monocytes. Instructed by local cues, these cells adopt unique transcriptional modules that impart tissue-specific functional identity (Varol et al., 2015). In the liver, Kupffer cells (KCs) dominate the homeostatic macrophage pool. They reside in the sinusoidal vessels and in the space of Disse, interacting with hepatic stellate cells (HSC) and hepatocytes (Bonnardel et al., 2019), where they act as sentinels and perform specialized accessory functions involving iron and lipid metabolism (Scott and Guilliams, 2018). Yet, the molecular cues governing KC differentiation and maintanence remain largly elusive. Embryonic lethality of COMMD10 deficiency has hampered the study of its function. Yet, utilizing conditional COMMD10 knockout mice we recently uncovered a role for COMMD10 in supporting phagolysosomal biogenesis and maturation in KCs and BM-derived macrophages infected with Staphylococcus aureus (Ben Shlomo et al., 2019). Here we show that COMMD10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10-deficiency in KCs and in other tissue resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6Chi monocytes. Transcriptional analysis of COMMD10-deficiet KCs reveales a notable reduction in genes encoding for translation initiation- and ribosomal complex proteins, for ubiquitin and the proteasome protein complex, and for key proteins of the mitochondrial respiration chain. These transcriptional alterations allude to protein stress and mitochondrial dysfunction, and hint at the reason of their premature death.
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Project description:A catalytic antioxidant (AEOL 10150) attenuates expression of inflammatory genes in stroke. White and grey matter in the distribution on the middle cerebral artery 6 hours after administration of the saline/catalytic antioxidant AEOL 10150 and ischemia/reperfusion of the MCAO; pooled mRNA from 6 brains. Keywords = stroke, antioxidant Keywords: repeat sample
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Project description:Monocytes are circulating myeloid immune precursor cells that are generated in the bone marrow (BM). Upon their release into the circulation, monocytes are recruited to inflammatory sites, where they differentiate into monocyte-derived effector cells. In absence of overt inflammation, monocytes also extravasate into selected tissues, where they complement tissue-resident macrophage compartments. Recent studies have uncovered binary developmental trajectories of monocytes in the BM with Neutrophil-like (NeuMo) and dendritic cell (DC)-like (DCMo) monocytes differentiating downstream of granulocyte-macrophage progenitors (GMP) and macrophage-dendritic cell progenitors (MDP), respectively (Weinreb et al., 2020; Yanez et al., 2017). Yet, the molecular cues that dictate BM monocyte differentiation remain incompletely understood. The COMMD (copper metabolism MURR1 domain) family includes 10 evolutionarily conserved proteins. Functions of COMMD proteins are still being defined, but they seem to play non-redundant roles in regulating transcription and protein trafficking. Utilizing conditional COMMD10 knockout mice we uncovered a role for COMMD10 in limiting inflammasome activation in Ly6Chi monocytes during experimental sepsis and colitis (Mouhadeb et al., 2018), and in supporting phagolysosomal biogenesis and maturation in KCs and BM-derived macrophages infected with Staphylococcus aureus (Ben Shlomo et al., 2019). Hence, these studies mark COMMD10 as a candidate mediator of monocyte and macrophage fate and immune responses. Here we studied the effect of COMMD10-deficiency on Ly6Chi monocyte differentiation. We show that COMMD10-deficiency in steady state Ly6Chi monocytes promotes a differentiation bias towards NeuMo fate.
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Project description:Hepatic macrophages play a central role in the initiation, progression and resolution of various liver diseases. Specifically, infiltrating Ly6Chi monocytes and their-derived macrophage (MoMFs) descendants prevail in acute or chronic liver injury, display marked transcriptional variance and provide crucial functional plasticity. A specific example of MoMFs are lipid associated macrophages (LAMs) involved in progression of metabolic liver disease (Remmerie et al., 2020). Recent studies have uncovered binary developmental trajectories of monocytes in the BM with Neutrophil-like (NeuMo) and dendritic cell (DC)-like (DCMo) monocytes (Weinreb et al., 2020; Yanez et al., 2017), hence further challenging our current comprehension of macrophage heterogeneity in the diseased liver. Yet, the molecular factors regulating their inflammatory versus restorative activity remains enigmatic. The COMMD (copper metabolism MURR1 domain) family includes 10 evolutionarily conserved proteins. Functions of COMMD proteins are still being defined, but they seem to play non-redundant roles in regulating transcription and protein trafficking. Utilizing conditional COMMD10 knockout mice we uncovered a role for COMMD10 in limiting inflammasome activation in Ly6Chi monocytes during experimental sepsis and colitis (Mouhadeb et al., 2018), and in supporting phagolysosomal biogenesis and maturation in KCs and BM-derived macrophages infected with Staphylococcus aureus (Ben Shlomo et al., 2019). Hence, these studies mark COMMD10 as a candidate mediator of monocyte and macrophage fate and immune responses. Here we studeid the effect of COMMD10-deficiency on Ly6Chi monocyte differentiation and inflammatory behaviour in the injured liver, using an acute model of acetaminophen-induced liver injury (AILI). Bulk RNAseq analysis of sorted Ly6Chi monocytes, comparing between COMMD10+ and COMMD10-deficient cells, revealed an increased differentiation bias of Ly6Chi monocytes towards NeuMo and LAM differentiation fates. Collectively, COMMD10 appears as an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.
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Project description:Hepatic macrophages play a central role in the initiation, progression and resolution of various liver diseases. Specifically, infiltrating Ly6Chi monocytes and their-derived macrophage (MoMFs) descendants prevail in acute or chronic liver injury, display marked transcriptional variance and provide crucial functional plasticity. A specific example of MoMFs are lipid associated macrophages (LAMs) involved in progression of metabolic liver disease (Remmerie et al., 2020). Recent studies have uncovered binary developmental trajectories of monocytes in the BM with Neutrophil-like (NeuMo) and dendritic cell (DC)-like (DCMo) monocytes (Weinreb et al., 2020; Yanez et al., 2017), hence further challenging our current comprehension of macrophage heterogeneity in the diseased liver. Yet, the molecular factors regulating their inflammatory versus restorative activity remains enigmatic. The COMMD (copper metabolism MURR1 domain) family includes 10 evolutionarily conserved proteins. Functions of COMMD proteins are still being defined, but they seem to play non-redundant roles in regulating transcription and protein trafficking. Utilizing conditional COMMD10 knockout mice we uncovered a role for COMMD10 in limiting inflammasome activation in Ly6Chi monocytes during experimental sepsis and colitis (Mouhadeb et al., 2018), and in supporting phagolysosomal biogenesis and maturation in KCs and BM-derived macrophages infected with Staphylococcus aureus (Ben Shlomo et al., 2019). Hence, these studies mark COMMD10 as a candidate mediator of monocyte and macrophage fate and immune responses. Here we studeis the effect of COMMD10-deficiency on Ly6Chi monocyte differentiation and inflammatory behaviour in the injured liver, using an acute model of acetaminophen-induced liver injury (AILI). Single cell RNAseq analysis of sorted Ly6Chi monocytes, comparing between COMMD10+ and COMMD10-deficient cells, revealed increased differentiation bias of Ly6Chi monocytes towards NeuMo and LAM differentiation fates. Collectively, COMMD10 appears as an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.
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