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Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis

ABSTRACT: In vitro studies associated oxidative phosphorylation (OXPHOS) with anti-inflammatory macrophages, while pro-inflammatory macrophages rely on glycolysis. However, the metabolic needs of macrophages in tissues (TMFs) to fulfil their homeostatic activities are incompletely understood. Here, we identified OXPHOS as highly discriminating process among TMFs from different tissues in homeostasis by analysis of RNAseq data, in both human and mouse. Impairing OXPHOS in TMFs via Tfam deletion differentially affected TMF populations. Tfam deletion resulted in reduction of alveolar macrophages (AMs) due to impaired lipid-handling capacity, leading to increased cholesterol content and cellular stress, causing cell cycle arrest in vivo. In obesity, Tfam depletion selectively ablated pro-inflammatory lipid-handling white adipose tissue macrophages (WAT-MFs), preventing insulin resistance and hepatosteatosis. Thus, OXPHOS, rather than glycolysis, distinguishes TMF populations and is critical for the maintenance of TMFs with a high lipid-handling activity, including pro-inflammatory WAT-MFs. This could provide a selective therapeutic targeting tool.

ORGANISM(S): Mus musculus

PROVIDER: GSE213268 | GEO | 2022/10/31

REPOSITORIES: GEO

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Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis

Project description:In vitro studies associated oxidative phosphorylation (OXPHOS) with anti-inflammatory macrophages, while pro-inflammatory macrophages rely on glycolysis. However, the metabolic needs of macrophages in tissues (TMFs) to fulfil their homeostatic activities are incompletely understood. Here, we identified OXPHOS as highly discriminating process among TMFs from different tissues in homeostasis by analysis of RNAseq data, in both human and mouse. Impairing OXPHOS in TMFs via Tfam deletion differentially affected TMF populations. Tfam deletion resulted in reduction of alveolar macrophages (AMs) due to impaired lipid-handling capacity, leading to increased cholesterol content and cellular stress, causing cell cycle arrest in vivo. In obesity, Tfam depletion selectively ablated pro-inflammatory lipid-handling white adipose tissue macrophages (WAT-MFs), preventing insulin resistance and hepatosteatosis. Thus, OXPHOS, rather than glycolysis, distinguishes TMF populations and is critical for the maintenance of TMFs with a high lipid-handling activity, including pro-inflammatory WAT-MFs. This could provide a selective therapeutic targeting tool.

2022-09-01 | ST002280 | MetabolomicsWorkbench

Classically-activated macrophages rely on glucose-derived glycerol and external fatty acid for TAG synthesis

Project description:Altered lipid metabolism in macrophages is associated with various important inflammatory conditions. Although lipid metabolism is an important target for therapeutic intervention, the metabolic requirement involved in lipid accumulation during pro-inflammatory activation of macrophages remains incompletely characterized. We show here that macrophage activation with IFNγ results in increased aerobic glycolysis, iNOS-dependent inhibition of respiration, and accumulation of triacylglycerol. Surprisingly, metabolite tracing with 13C-labeled glucose revealed that the glucose contributed to the glycerol groups in triacylglycerol (TAG), rather than to de novo synthesis of fatty acids. This is in stark contrast to the otherwise similar metabolism of cancer cells, and previous results obtained in activated macrophages and dendritic cells. Our results establish a novel metabolic pathway whereby glucose provides glycerol to the headgroup of TAG during classical macrophage activation.

2020-02-27 | PXD017148 | Pride

Regulation of Macrophage Foam Cell Formation during Nitrogen Mustard (NM)-Induced Pulmonary Fibrosis by Lung Lipids

Project description:Nitrogen mustard (NM) is a vesicant known to target the lung, causing acute injury which progresses to fibrosis. Evidence suggests that activated macrophages contribute to the pathologic response to NM. In these studies, we analyzed the role of lung lipids generated following NM exposure on macrophage activation and phenotype. Treatment of rats with NM (0.125 mg/kg, i.t.) resulted in a time-related increase in enlarged vacuolated macrophages in the lung. At 28 d post exposure, macrophages stained positively for Oil Red O, a marker of neutral lipids. This was correlated with an accumulation of oxidized phospholipids in lung macrophages and epithelial cells, and an increase in bronchoalveolar lavage fluid (BAL) phospholipids. RNA-sequencing analysis revealed that lipid handling pathways under control of the transcription factors LXR, FXR and PPAR-ɣ were significantly altered following NM exposure. Whereas at 1-3 d post NM, FXR and the downstream oxidized low density lipoprotein receptor, Cd36, were increased, Lxr and the lipid extrusion pump targets, Abca1 and Abcg1 were reduced. Treatment of naïve lung macrophages with lipid enriched fractions of BAL collected 3 d after NM resulted in upregulation of Nos2, Apoe and Ptgs2, markers of pro-inflammatory activation, while lipid-enriched BAL collected 28 d post NM upregulated expression of the anti-inflammatory markers, Il10, Cd163, and Cx3cr1, and induced the formation of lipid-laden foamy macrophages. These data suggest that NM-induced alterations in lipid handling and metabolism drive macrophage foam cell formation, potentially contributing to the development of pulmonary fibrosis.

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Project description:Microbiota contributes to induction of type 2 diabetes by high-fat/high-sugar (HFHS), but which organs/pathways are impacted by microbiota remains unknown. Using multi-organ network and transkingdom analyses, we found that microbiota-dependent. impairment of OXPHOS /mitochondria in white adipose tissue (WAT) plays a primary role in regulating systemic glucose metabolism. The follow-up analysis established that Mmp12+ macrophages link microbiota-dependent inflammation and OXPHOS damage in WAT. Moreover, the molecular signature of Mmp12+ macrophages in WAT was associated with insulin resistance in obese patients. Next, we tested functional effects of MMP12 and found that Mmp12 genetic deficiency or MMP12 inhibition improved glucose metabolism in conventional, but not in germfree mice. MMP12 treatment induced insulin resistance in adipocytes. TLR2-ligands present in Oscillibacter valericigenes bacteria, which are expanded by HFHS, induce Mmp12 in WAT macrophages in a MYD88-ATF3-dependent manner. Thus, HFHS induces Mmp12+ macrophages and MMP12, representing a microbiota-dependent bridge between inflammation and mitochondrial damage in WAT and causing insulin resistance. doi: https://doi.org/10.1084/jem.20220017

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Project description:Paper abstract: Microbiota contribute to the induction of type 2 diabetes by high-fat/high-sugar (HFHS) diet, but which organs/pathways are impacted by microbiota remain unknown. Using multiorgan network and transkingdom analyses, we found that microbiotadependent impairment of OXPHOS/mitochondria in white adipose tissue (WAT) plays a primary role in regulating systemic glucose metabolism. The follow-up analysis established that Mmp12+ macrophages link microbiota-dependent inflammation and OXPHOS damage in WAT. Moreover, the molecular signature of Mmp12+ macrophages in WAT was associated with insulin resistance in obese patients. Next, we tested the functional effects of MMP12 and found that Mmp12 genetic deficiency or MMP12 inhibition improved glucose metabolism in conventional, but not in germ-free mice. MMP12 treatment induced insulin resistance in adipocytes. TLR2-ligands present in Oscillibacter valericigenes bacteria, which are expanded by HFHS, induce Mmp12 in WAT macrophages in a MYD88-ATF3–dependent manner. Thus, HFHS induces Mmp12+ macrophages and MMP12, representing a microbiota-dependent bridge between inflammation and mitochondrial damage in WAT and causing insulin resistance.

2022-10-13 | GSE215226 | GEO

Treatment of RAW 264.7 cells with Oscillibater valericigenes

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Mural Cell ZFP423 Controls Adipose Tissue Macrophage Accrual in Obesity [ChIP-seq]

Project description:Chronic low-grade visceral white adipose tissue (WAT) inflammation is a hallmark of metabolic syndrome in obesity. Here, we demonstrate that a specific subpopulation of adipose tissue perivascular (PDGFRb+) stromal cells, termed “fibro-inflammatory progenitors” (FIPs), activate pro-inflammatory signaling cascades shortly after the onset of high-fat diet feeding of mice and control the accumulation of pro-inflammatory macrophages in WAT. The activation of FIPs is mediated by the downregulation of ZFP423, identified here as a transcriptional co-regulator of NFkB. Biochemical analysis of ZFP423-protein complexes and ChIP-seq analysis reveal that ZFP423 suppresses the DNA-binding capacity of the p65 subunit of NFkB by inducing a co-regulator switch. Doxycycline-inducible expression of Zfp423 in PDGFRb+ cells suppresses inflammatory signaling in FIPs and attenuates macrophage accumulation within visceral WAT of obese mice. Conversely, inducible inactivation of Zfp423 in PDGFRb+ cells increases FIP activity, exacerbates adipose macrophage accrual, and promotes WAT dysfunction in obese mice. These studies implicate mural cells as sentinels and gatekeepers of adipose tissue inflammation in obesity.

2020-09-01 | GSE134868 | GEO

Nuclear receptor, RORa plays a critical role in obesity-associated inflammation, hepatic steatosis, and insulin resistance

Project description:We demonstrated that RORa-deficient staggerer mice (RORasg/sg) fed with a high fat diet (HFD) showed reduced adiposity and hepatic triglyceride levels compared to wild type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of RORasg/sg mice. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of RORasg/sg mice fed with a HFD. The infiltration of macrophages and the expression of many immune-response and pro-inflammatory genes, including those encoding various chemo/cytokines, toll-like receptors, and TNF signaling proteins, were significantly reduced in RORasg/sg WAT. Moreover, RORasg/sg mice fed with a HFD were protected from the development of insulin resistance. Together, these results indicate that RORa plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, RORa may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. Liver and white adipose tissue (WAT) total RNAs were purified from 5 WT and 5 RORasg/sg (natural deletion of RORa gene in mice) mice fed with a high fat diet for 6 weeks. Then samples were applied on Agilent mouse genome chip.

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RNA-Seq of human AML cell line, HL-60 and its mitoxantrone resistant subline HL60/MX2

Project description:Alteration in metabolic repertoire is commonly associated with resistance phenotype. Although it’s a common phenotype, not much efforts have been undertaken to design effective strategies to target the metabolic drift in such cancerous cells and especially with drug resistant properties. In our study, we identified that drug resistant AML cell line HL-60/MX2 do not follow classical Warburg effect, instead these cells exhibit drastically low levels of aerobic glycolysis. Biochemical analysis confirms reduced glucose consumption and lactic acid production by resistant population with no differences in glutamine consumption. Raman spectroscopy revealed increased lipid and cytochrome content in resistant cells which were also visualized in the form of lipid droplets by Raman mapping, electron microscopy and lipid specific staining. Gene set enrichment analysis data from both the cell lines revealed significant enrichment of lipid metabolic pathways in HL-60/MX2 cells. Further drug resistant cells possess higher mitochondrial activity and increased OXPHOS suggested the role of fatty acid metabolism as energy source which was confirmed by increased rate of fatty acid oxidation. Pharmacological inhibition of fatty acid oxidation using Etomoxir affected the colony formation ability of resistant cells and inhibition of OXPHOS using Antimycin-A increased the sensitivity of resistant cells to chemotherapeutic drug, demonstrating requirement of fatty acid metabolism and increased dependency on OXPHOS by resistant leukemic cells for tumorigenicity.

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