A past and present overview of macrophage metabolism and functional outcomes

Curi, Rui; Mendes, Renata de Siqueira; Crispin, Luiz Aurélio de Campos; Norata, Giuseppe Danilo; Sampaio, Sandra Coccuzzo; Newsholme, Philip

doi:10.1042/cs20170220

Cited by 81 publications

(68 citation statements)

References 91 publications

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“…In addition to fatty acid oxidation and glycolysis, oxidative phosphorylation can be fueled by glutamine, the most abundant circulating amino acid in mammals and a major TCA substrate via its catabolism to α-ketoglutarate (αKG) (Newsholme et al 1986;Fan et al 2013;Curi et al 2017). We found that, unlike control macrophages, MPKO macrophages were unable to effectively respire using glutamine as fuel (Fig.…”

Section: Pparγ Is Required For Respiration From Glutaminementioning

confidence: 92%

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

et al. 2018

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The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.

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Section: Pparγ Is Required For Respiration From Glutaminementioning

confidence: 92%

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

et al. 2018

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“…Monocytes bind to activated endothelium, migrate into the intimal layer and take up lipoproteins to become macrophages. Monocyte/macrophages can induce the release of inflammatory factors, promote AS formation and induce plaque rupture, leading to the occurrence of acute coronary syndrome (ACS) 9,[12][13][14][15] . Previous study showed that monocytes are functionally different in hyperlipidemia 16 .…”

Section: Discussionmentioning

confidence: 99%

Monocyte to high-density lipoprotein ratio was associated with the severity of coronary artery disease: results from a large cohort study

H¹,

Wang²,

Huo³

et al. 2020

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Background: Monocyte to high-density lipoprotein ratio (MHR) was a recently emerged lipid biomarker, might reflect the inflammation level and the lipid profile in a quantitative manner.We aimed to investigate the association of MHR with the severity of coronary artery disease (CAD), and the ability of MHR in predicting severe CAD and acute atherothrombosis events. Methods: A total of 3930 CAD patients and 1020 non-CAD patients presented consecutively to our hospital for coronary angiography. The CAD patients were classified into four groups according to the quartile of the MHR (≤0.28, N=1218; 0.28-0.39, N=1262; 0.39-0.53, N=1209; >0.53, N=1261). CAD severity was quantified according to the Gensini score. A receiver operating characteristic (ROC) curve analysis was also performed to predict severe CAD and acute coronary thrombotic events. Results: MHR was significantly higher in the CAD group than in the non-CAD group (0.45 ± 0.22 vs. 0.35 ± 0.17, p<0.001) and had a significant positive correlation with Gensini score. Compared with lower MHR value, a MHR in the fourth quartile was strongly associated with severe CAD and acute coronary thrombotic event after adjusting for baseline factors. Receiver-operating characteristic (ROC) curve analysis showed that combination of MHR and traditional risk predictors could better predict severe CAD especially acute coronary thrombosis events such as non-ST-elevation myocardial infarction (NSTEMI) and acute ST-segment elevation myocardial infarction (ASTEMI). Conclusions: MHR was positive associated with the prevalence and severity of CAD. Moreover, MHR may be a prognostic marker for acute atherothrombosis events.

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“…Macrophages depend to varying degrees upon glutamine, glucose and fatty acids as fuels [136] and glutamine is an important immune regulator [137]. 14 different solute carriers from 4 families have been shown to transport glutamine [138].…”

Section: Expression Of Solute Carriers and Metabolism Genes In Macropmentioning

confidence: 99%

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

Hume

2020

Preprint

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The mononuclear phagocyte system (MPS) is a family of cells including progenitors, circulating blood monocytes, resident tissue macrophages and dendritic cells (DC) present in every tissue in the body. To test the relationships between markers and transcriptomic diversity in the MPS, we collected from NCBI-GEO >500 quality RNA-seq datasets generated from mouse MPS cells isolated from multiple tissues. The primary data were randomly down-sized to a depth of 10 million reads and requantified. The resulting dataset was clustered using the network analysis tool Graphia. A sample-to-sample matrix revealed that MPS populations could be separated based upon tissue of origin. Cells identified as classical DC subsets, cDC1 and cDC2, and lacking Fcgr1 (CD64), were centrally-located within the MPS cluster and no more distinct than other MPS cell types. A gene-to-gene correlation matrix identified large generic co-expression clusters associated with MPS maturation and innate immune function. Smaller co-expression clusters including the transcription factors that drive them showed higher expression within defined isolated cells, including macrophages and DC from specific tissues. They include a cluster containing Lyve1 that implies a function in endothelial cell homeostasis, a cluster of transcripts enriched in intestinal macrophages and a generic cDC cluster associated with Ccr7. However, transcripts encoding many other putative MPS subset markers including Adgre1, Itgax, Itgam, Clec9a, Cd163, Mertk, Retnla and H2-A/E (class II MHC) clustered idiosyncratically and were not correlated with underlying functions. The data provide no support for the concept of markers of M2 polarization or the specific adaptation of DC to present antigen to T cells. Co-expression of immediate early genes (e.g. Egr1, Fos, Dusp1) and inflammatory cytokines and chemokines (Tnf, Il1b, Ccl3/4) indicated that all tissue disaggregation protocols activate MPS cells. Tissue-specific expression clusters indicated that all cell isolation procedures also co-purify other unrelated cell types that may interact with MPS cells in vivo. Comparative analysis of public RNA-seq and single cell RNA-seq data from the same lung cell populations showed that the extensive heterogeneity implied by the global cluster analysis may be even greater at a single cell level with few markers strongly correlated with each other. This analysis highlights the power of large datasets to identify the diversity of MPS cellular phenotypes, and the limited predictive value of surface markers to define lineages, functions or subpopulations.

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A past and present overview of macrophage metabolism and functional outcomes

Cited by 81 publications

References 91 publications

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism

Monocyte to high-density lipoprotein ratio was associated with the severity of coronary artery disease: results from a large cohort study

Transcriptional network analysis of transcriptomic diversity in resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system

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