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1.
Redox Biol ; 70: 103054, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38309122

RESUMO

Inflammatory macrophages are key drivers of atherosclerosis that can induce rupture-prone vulnerable plaques. Skewing the plaque macrophage population towards a more protective phenotype and reducing the occurrence of clinical events is thought to be a promising method of treating atherosclerotic patients. In the current study, we investigate the immunomodulatory properties of itaconate, an immunometabolite derived from the TCA cycle intermediate cis-aconitate and synthesised by the enzyme Aconitate Decarboxylase 1 (ACOD1, also known as IRG1), in the context of atherosclerosis. Ldlr-/- atherogenic mice transplanted with Acod1-/- bone marrow displayed a more stable plaque phenotype with smaller necrotic cores and showed increased recruitment of monocytes to the vessel intima. Macrophages from Acod1-/- mice contained more lipids whilst also displaying reduced induction of apoptosis. Using multi-omics approaches, we identify a metabolic shift towards purine metabolism, in addition to an altered glycolytic flux towards production of glycerol for triglyceride synthesis. Overall, our data highlight the potential of therapeutically blocking ACOD1 with the aim of stabilizing atherosclerotic plaques.


Assuntos
Aterosclerose , Placa Aterosclerótica , Humanos , Animais , Camundongos , Placa Aterosclerótica/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Succinatos/farmacologia , Macrófagos/metabolismo
2.
Immunol Lett ; 265: 23-30, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38142781

RESUMO

Immunometabolism has been unveiled in the last decade to play a major role in controlling macrophage metabolism and inflammation. There has been a constant effort to understand the immunomodulating properties of regulated metabolites during inflammation with the aim of controlling and re-wiring aberrant macrophages in inflammatory diseases. M-CSF and GM-CSF-differentiated macrophages play a key role in mounting successful innate immune responses. When a resolution phase is not achieved however, GM-CSF macrophages contribute substantially more towards an adverse inflammatory milieu than M-CSF macrophages, consequently driving disease progression. Whether there are specific immunometabolites that determine the homoeostatic or inflammatory nature of M-CSF and GM-CSF-differentiated macrophages is still unknown. As such, we performed metabolomics analysis on LPS and IL-4-stimulated M-CSF and GM-CSF-differentiated human macrophages to identify differentially accumulating metabolites. Adenine was distinguished as a metabolite significantly higher in M-CSF-differentiated macrophages after both LPS or IL-4 stimulation. Human macrophages treated with adenine before LPS stimulation showed a reduction in inflammatory gene expression, cytokine secretion and surface marker expression. Adenine caused macrophages to become more quiescent by lowering glycolysis and OXPHOS which resulted in reduced ATP production. Moreover, typical metabolite changes seen during LPS-induced macrophage metabolic reprogramming were absent in the presence of adenine. Phosphorylation of metabolic signalling proteins AMPK, p38 MAPK and AKT were not responsible for the suppressed metabolic activity of adenine-treated macrophages. Altogether, in this study we highlight the immunomodulating capacity of adenine in human macrophages and its function in driving cellular quiescence.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Fator Estimulador de Colônias de Macrófagos , Humanos , Adenina/metabolismo , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Inflamação/metabolismo , Interleucina-4/metabolismo , Lipopolissacarídeos/farmacologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos
3.
Cell Metab ; 35(11): 1847-1848, 2023 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-37939654

RESUMO

Macrophages not only secure host defense via phagocytosis but also play a key role in tissue homeostasis. A comprehensive study by Fritsch et al. reveals a novel mechanism by which macrophages in the colon deliver polyamines to epithelial cells to support self-renewal of the epithelium during periods of high proliferation.


Assuntos
Colo , Células Epiteliais , Epitélio , Macrófagos , Fagocitose
4.
Cell Death Dis ; 14(8): 536, 2023 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-37604805

RESUMO

Acinar cell dedifferentiation is one of the most notable features of acute and chronic pancreatitis. It can also be the initial step that facilitates pancreatic cancer development. In the present study, we further decipher the precise mechanisms and regulation using primary human cells and murine experimental models. Our RNAseq analysis indicates that, in both species, early acinar cell dedifferentiation is accompanied by multiple pathways related to cell survival that are highly enriched, and where SLC7A11 (xCT) is transiently upregulated. xCT is the specific subunit of the cystine/glutamate antiporter system xC-. To decipher its role, gene silencing, pharmacological inhibition and a knock-out mouse model were used. Acinar cells with depleted or reduced xCT function show an increase in ferroptosis relating to lipid peroxidation. Lower glutathione levels and more lipid ROS accumulation could be rescued by the antioxidant N-acetylcysteine or the ferroptosis inhibitor ferrostatin-1. In caerulein-induced acute pancreatitis in mice, xCT also prevents lipid peroxidation in acinar cells. In conclusion, during stress, acinar cell fate seems to be poised for avoiding several forms of cell death. xCT specifically prevents acinar cell ferroptosis by fueling the glutathione pool and maintaining ROS balance. The data suggest that xCT offers a druggable tipping point to steer the acinar cell fate in stress conditions.


Assuntos
Ferroptose , Pancreatite , Humanos , Animais , Camundongos , Células Acinares , Doença Aguda , Ferroptose/genética , Pancreatite/genética , Espécies Reativas de Oxigênio , Ácido Glutâmico
5.
Curr Opin Biotechnol ; 83: 102976, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37515937

RESUMO

2-hydroxyglutarate (2HG) is a biproduct of the Krebs cycle, which exists in a D- and L- enantiomer and is structurally similar to α-ketoglutarate. Both 2HG enantiomers have been described to accumulate in diverse cancer and immune cells and can influence cell fate and function. While D-2HG was originally considered as an 'oncometabolite' that aberrantly builds up in certain cancers, it is becoming clear that it also physiologically accumulates in immune cells and regulates immune function. Conversely, L-2HG is considered as an 'immunometabolite' due to its induction and regulatory function in T cells, but it can also be induced in certain cancers. Here, the authors review the effects of both 2HG enantiomers on immune cells within the tumor microenvironment.


Assuntos
Neoplasias , Humanos , Glutaratos , Ácidos Cetoglutáricos , Estereoisomerismo , Mutação , Microambiente Tumoral
7.
Redox Biol ; 59: 102591, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36574745

RESUMO

Pathological conditions associated with dysfunctional wound healing are characterized by impaired remodelling of extracellular matrix (ECM), increased macrophage infiltration, and chronic inflammation. Macrophages also play an important role in wound healing as they drive wound closure by secretion of molecules like transforming growth factor beta-1 (TGF-ß). As the functions of macrophages are regulated by their metabolism, local administration of small molecules that alter this might be a novel approach for treatment of wound-healing disorders. Itaconate is a tricarboxylic acid (TCA) cycle-derived metabolite that has been associated with resolution of macrophage-mediated inflammation. However, its effects on macrophage wound healing functions are unknown. In this study, we investigated the effects of the membrane-permeable 4-octyl itaconate (4-OI) derivative on ECM scavenging by cultured human blood monocyte-derived macrophages (hMDM). We found that 4-OI reduced signalling of p38 mitogen-activated protein kinase (MAPK) induced by the canonical immune stimulus lipopolysaccharide (LPS). Likely as a consequence of this, the production of the inflammatory mediators like tumor necrosis factor (TNF)-α and cyclooxygenase (COX)-2 were also reduced. On the transcriptional level, 4-OI increased expression of the gene coding for TGF-ß (TGFB1), whereas expression of the collagenase matrix metalloprotease-8 (MMP8) was reduced. Furthermore, surface levels of the anti-inflammatory marker CD36, but not CD206 and CD11c, were increased in these cells. To directly investigate the effect of 4-OI on scavenging of ECM by macrophages, we developed an assay to measure uptake of fibrous collagen. We observed that LPS promoted collagen uptake and that this was reversed by 4-OI-induced signaling of nuclear factor erythroid 2-related factor 2 (NRF2), a regulator of cellular resistance to oxidative stress and the reduced glycolytic capacity of the macrophage. These results indicate that 4-OI lowers macrophage inflammation, likely promoting a more wound-resolving phenotype.


Assuntos
Lipopolissacarídeos , Macrófagos , Humanos , Lipopolissacarídeos/efeitos adversos , Macrófagos/metabolismo , Inflamação/metabolismo , Fenótipo , Fator de Necrose Tumoral alfa/metabolismo , Ciclo-Oxigenase 2/metabolismo , Colágeno/metabolismo , Fator de Crescimento Transformador beta/metabolismo
8.
Biochim Biophys Acta Mol Basis Dis ; 1868(9): 166427, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35526742

RESUMO

Macrophages undergo extensive metabolic rewiring upon activation which assist the cell in roles beyond energy production and synthesis of anabolic building blocks. So-called immunometabolites that accumulate upon immune activation can serve as co-factors for enzymes and can act as signaling molecules to modulate cellular processes. As such, the Krebs-cycle-associated metabolites succinate, itaconate and alpha-ketoglutarate (αKG) have emerged as key regulators of macrophage function. Here, we describe that 2-hydroxyglutarate (2HG), which is structurally similar to αKG and exists as two enantiomers, accumulates during later stages of LPS-induced inflammatory responses in mouse and human macrophages. D-2HG was the most abundant enantiomer in macrophages and its LPS-induced accumulation followed the induction of Hydroxyacid-Oxoacid Transhydrogenase (HOT). HOT interconverts αKG and gamma-hydroxybutyrate into D-2HG and succinic semialdehyde, and we here identified this enzyme as being immune-responsive and regulated during the course of macrophage activation. The buildup of D-2HG may be further explained by reduced expression of D-2HG Dehydrogenase (D2HGDH), which converts D-2HG back into αKG, and showed inverse kinetics with HOT and D-2HG levels. We tested the immunomodulatory effects of D-2HG during LPS-induced inflammatory responses by transcriptomic analyses and functional profiling of D-2HG-pre-treated macrophages in vitro and mice in vivo. Together, these data suggest a role for D-2HG in the negative feedback regulation of inflammatory signaling during late-stage LPS-responses in vitro and as a regulator of local and systemic inflammatory responses in vivo. Finally, we show that D-2HG likely exerts distinct anti-inflammatory effects, which are in part independent of αKG-dependent dioxygenase inhibition. Together, this study reveals an immunometabolic circuit resulting in the accumulation of the immunomodulatory metabolite D-2HG that can inhibit inflammatory macrophage responses.


Assuntos
Anti-Inflamatórios , Glutaratos , Macrófagos , Receptor 4 Toll-Like , Animais , Anti-Inflamatórios/farmacologia , Glutaratos/farmacologia , Humanos , Ácidos Cetoglutáricos/metabolismo , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos
9.
Cell Rep Methods ; 2(4): 100192, 2022 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-35497494

RESUMO

Macrophages are dynamic immune cells that can adopt several activation states. Fundamental to these functional activation states is the regulation of cellular metabolic processes. Especially in mice, metabolic alterations underlying pro-inflammatory or homeostatic phenotypes have been assessed using various techniques. However, researchers new to the field may encounter ambiguity in choosing which combination of techniques is best suited to profile immunometabolism. To address this need, we have developed a toolbox to assess cellular metabolism in a semi-high-throughput 96-well-plate-based format. Application of the toolbox to activated mouse and human macrophages enables fast metabolic pre-screening and robust measurement of extracellular fluxes, mitochondrial mass and membrane potential, and glucose and lipid uptake. Moreover, we propose an application of SCENITH technology for ex vivo metabolic profiling. We validate established activation-induced metabolic rewiring in mouse macrophages and report new insights into human macrophage metabolism. By thoroughly discussing each technique, we hope to guide readers with practical workflows for investigating immunometabolism.


Assuntos
Glicólise , Macrófagos , Humanos , Animais , Camundongos , Homeostase , Mitocôndrias/metabolismo , Ativação de Macrófagos
10.
Cell Mol Gastroenterol Hepatol ; 13(4): 1243-1253, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34875393

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a devastating type of cancer. While many studies have shed light into the pathobiology of PDAC, the nature of PDAC's cell of origin remains under debate. Studies in adult pancreatic tissue have unveiled a remarkable exocrine cell plasticity including transitional states, mostly exemplified by acinar to ductal cell metaplasia, but also with recent evidence hinting at duct to basal cell transitions. Single-cell RNA sequencing has further revealed intrapopulation heterogeneity among acinar and duct cells. Transcriptomic and epigenomic relationships between these exocrine cell differentiation states and PDAC molecular subtypes have started to emerge, suggesting different ontogenies for different tumor subtypes. This review sheds light on these diverse aspects with particular focus on studies with human cells. Understanding the "masked ball" of exocrine cells at origin of PDAC and leaving behind the binary acinar vs duct cell classification may significantly advance our insights in PDAC biology.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Células Acinares/patologia , Carcinoma Ductal Pancreático/patologia , Plasticidade Celular , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas
11.
Cell Rep ; 37(13): 110171, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34965415

RESUMO

Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although metabolism influences macrophage function, studies on the metabolic characteristics of ex vivo tumor-associated macrophage (TAM) subsets are rather limited. Using transcriptomic and metabolic analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-IIhi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-IIlo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-IIlo TAMs, while it decreases the metabolic activity of MHC-IIhi TAMs. Lactate subtly affects the transcriptome of MHC-IIlo TAMs, increases L-arginine metabolism, and enhances the T cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as a carbon source and metabolic and functional regulator of TAMs.


Assuntos
Carcinoma Pulmonar de Lewis/patologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Lactatos/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos T/imunologia , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Animais , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Glicólise , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Complexo Principal de Histocompatibilidade , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Transcriptoma
12.
Trends Mol Med ; 27(12): 1095-1105, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34635427

RESUMO

ATP-citrate lyase (Acly) is the target of the new class low-density lipoprotein-cholesterol (LDL-C)-lowering drug bempedoic acid (BA). Acly is a key metabolic enzyme synthesizing acetyl-CoA as the building block of cholesterol and fatty acids. Treatment with BA lowers circulating lipid levels and reduces systemic inflammation, suggesting a dual benefit of this drug for atherosclerosis therapy. Recent studies have shown that targeting Acly in macrophages can attenuate inflammatory responses and decrease atherosclerotic plaque vulnerability. Therefore, it could be beneficial to extend the application of Acly inhibition from solely lipid-lowering by liver-specific inhibition to also targeting macrophages in atherosclerosis. Here, we outline the possibilities of targeting Acly and describe the future needs to translate these findings to the clinic.


Assuntos
ATP Citrato (pro-S)-Liase , Aterosclerose , ATP Citrato (pro-S)-Liase/metabolismo , Trifosfato de Adenosina , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , LDL-Colesterol/uso terapêutico , Humanos , Complexos Multienzimáticos , Oxo-Ácido-Liases
13.
J Immunol ; 207(2): 555-568, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34233910

RESUMO

As key cells of the immune system, macrophages coordinate the activation and regulation of the immune response. Macrophages present a complex phenotype that can vary from homeostatic, proinflammatory, and profibrotic to anti-inflammatory phenotypes. The factors that drive the differentiation from monocyte to macrophage largely define the resultant phenotype, as has been shown by the differences found in M-CSF- and GM-CSF-derived macrophages. We explored alternative inflammatory mediators that could be used for in vitro differentiation of human monocytes into macrophages. IFN-γ is a potent inflammatory mediator produced by lymphocytes in disease and infections. We used IFN-γ to differentiate human monocytes into macrophages and characterized the cells at a functional and proteomic level. IFN-γ alone was sufficient to generate macrophages (IFN-γ Mϕ) that were phagocytic and responsive to polarization. We demonstrate that IFN-γ Mϕ are potent activators of T lymphocytes that produce IL-17 and IFN-γ. We identified potential markers (GBP-1, IP-10, IL-12p70, and IL-23) of IFN-γ Mϕ and demonstrate that these markers are enriched in the skin of patients with inflamed psoriasis. Collectively, we show that IFN-γ can drive human monocyte to macrophage differentiation, leading to bona fide macrophages with inflammatory characteristics.


Assuntos
Diferenciação Celular/fisiologia , Inflamação/metabolismo , Interferon gama/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Psoríase/metabolismo , Biomarcadores/metabolismo , Células Cultivadas , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Fenótipo , Proteômica/métodos , Pele/metabolismo
14.
Cancers (Basel) ; 13(12)2021 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-34205266

RESUMO

Cancer cells rely on ATP-citrate lyase (Acly)-derived acetyl-CoA for lipid biogenesis and proliferation, marking Acly as a promising therapeutic target. However, inhibitors may have side effects on tumor-associated macrophages (TAMs). TAMs are innate immune cells abundant in the tumor microenvironment (TME) and play central roles in tumorigenesis, progression and therapy response. Since macrophage Acly deletion was previously shown to elicit macrophages with increased pro- and decreased anti-inflammatory responses in vitro, we hypothesized that Acly targeting may elicit anti-tumor responses in macrophages, whilst inhibiting cancer cell proliferation. Here, we used a myeloid-specific knockout model to validate that absence of Acly decreases IL-4-induced macrophage activation. Using two distinct tumor models, we demonstrate that Acly deletion slightly alters tumor immune composition and TAM phenotype in a tumor type-dependent manner without affecting tumor growth. Together, our results indicate that targeting Acly in macrophages does not have detrimental effects on myeloid cells.

15.
Trends Cancer ; 7(8): 666-667, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34183306

RESUMO

Isocitrate dehydrogenase (IDH) mutations produce high levels of the 'oncometabolite' R-2-hydroxyglutarate (R-2-HG) and play a key role in the initiation and progression of glioma tumors in the brain. A recent study in Nature Cancer by Friedrich et al. describes how IDH-mutant-derived R-2-HG elicits an immunosuppressive phenotype in glioma-associated macrophages. As such, the authors uncovered a new vulnerability that can be exploited for therapy.


Assuntos
Neoplasias Encefálicas , Isocitrato Desidrogenase , Glutaratos , Humanos , Macrófagos
16.
Front Immunol ; 12: 669920, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981315

RESUMO

Macrophages are highly plastic, key regulators of inflammation. Deregulation of macrophage activation can lead to excessive inflammation as seen in inflammatory disorders like atherosclerosis, obesity, multiple sclerosis and sepsis. Targeting intracellular metabolism is considered as an approach to reshape deranged macrophage activation and to dampen the progression of inflammatory disorders. ATP citrate lyase (Acly) is a key metabolic enzyme and an important regulator of macrophage activation. Using a macrophage-specific Acly-deficient mouse model, we investigated the role of Acly in macrophages during acute and chronic inflammatory disorders. First, we performed RNA sequencing to demonstrate that Acly-deficient macrophages showed hyperinflammatory gene signatures in response to acute LPS stimulation in vitro. Next, we assessed endotoxin-induced peritonitis in myeloid-specific Acly-deficient mice and show that, apart from increased splenic Il6 expression, systemic and local inflammation were not affected by Acly deficiency. Also during obesity, both chronic low-grade inflammation and whole-body metabolic homeostasis remained largely unaltered in mice with Acly-deficient myeloid cells. Lastly, we show that macrophage-specific Acly deletion did not affect the severity of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis. These results indicate that, despite increasing inflammatory responses in vitro, macrophage Acly deficiency does not worsen acute and chronic inflammatory responses in vivo. Collectively, our results indicate that caution is warranted in prospective long-term treatments of inflammatory disorders with macrophage-specific Acly inhibitors. Together with our earlier observation that myeloid Acly deletion stabilizes atherosclerotic lesions, our findings highlight that therapeutic targeting of macrophage Acly can be beneficial in some, but not all, inflammatory disorders.


Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Encefalomielite Autoimune Experimental/enzimologia , Inflamação/enzimologia , Macrófagos/enzimologia , Peritonite/enzimologia , ATP Citrato (pro-S)-Liase/genética , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Inflamação/etiologia , Inflamação/genética , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito , Obesidade/complicações , Fragmentos de Peptídeos , Peritonite/induzido quimicamente , Peritonite/genética , Peritonite/imunologia , Fenótipo , Transdução de Sinais
17.
Cell Metab ; 33(3): 468-470, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33657391

RESUMO

As age is the greatest risk factor for the development of most prevalent chronic diseases, there is an enormous interest in understanding the process of aging, with the hope of delaying or preventing age-related comorbidities. Along these lines, a recent study by Minhas et al. (2021) describes how aged macrophages downregulate glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), inducing an energy-deficient state that compromises macrophage function and supports maladaptive inflammation that together cause brain dysfunction.


Assuntos
Envelhecimento Saudável , Glicólise , Macrófagos/metabolismo , Mitocôndrias/metabolismo , Fosforilação Oxidativa
18.
Nat Biotechnol ; 39(2): 186-197, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32868913

RESUMO

Cellular metabolism regulates immune cell activation, differentiation and effector functions, but current metabolic approaches lack single-cell resolution and simultaneous characterization of cellular phenotype. In this study, we developed an approach to characterize the metabolic regulome of single cells together with their phenotypic identity. The method, termed single-cell metabolic regulome profiling (scMEP), quantifies proteins that regulate metabolic pathway activity using high-dimensional antibody-based technologies. We employed mass cytometry (cytometry by time of flight, CyTOF) to benchmark scMEP against bulk metabolic assays by reconstructing the metabolic remodeling of in vitro-activated naive and memory CD8+ T cells. We applied the approach to clinical samples and identified tissue-restricted, metabolically repressed cytotoxic T cells in human colorectal carcinoma. Combining our method with multiplexed ion beam imaging by time of flight (MIBI-TOF), we uncovered the spatial organization of metabolic programs in human tissues, which indicated exclusion of metabolically repressed immune cells from the tumor-immune boundary. Overall, our approach enables robust approximation of metabolic and functional states in individual cells.


Assuntos
Metaboloma , Análise de Célula Única , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Humanos , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos/imunologia , Análise do Fluxo Metabólico
19.
Transl Res ; 230: 123-138, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33166696

RESUMO

An increasing body of evidence shows a role for macrophages and monocytes (as their precursors) in hypertension, but with conflicting results with regard to whether they are protective or harmful. Therefore, we systematically reviewed the effect of macrophage interventions on blood pressure in animal models, to explore which factors determine the blood pressure increasing vs. decreasing effect. A search in PubMED and EMBASE yielded 9620 records, 26 of which were included. Eighteen studies (involving 22 different experiments (k = 22)) performed macrophage depletion, whereas 12 studies specifically deleted certain macrophage proteins. The blood pressure effects of macrophage depletion were highly various and directed toward both directions, as expected, which could not be reduced to differences in animal species or methods of hypertension induction. Prespecified subgroup analysis did reveal a potential role for the route in which the macrophage-depleting agent is being administrated (intraperitoneal vs intravenous subgroup difference of P = 0.07 (k = 22), or P < 0.001 in studies achieving considerable (ie, >50%) depletion (k = 18)). Along with findings from specific macrophage protein deletion studies-showing that deletion of one single macrophage protein (like TonEBP, endothelin-B, EP4, NOX-2 and the angiotensin II type 1 receptor) can alter blood pressure responses to hypertensive stimuli-the indication that each route has its specific depletion pattern regarding targeted tissues and macrophage phenotypes suggests a determinative role for these features. These hypothesis-generating results encourage more detailed depletion characterization of each technique by direct experimental comparisons, providing a chance to obtain more knowledge on which macrophages are beneficial versus detrimental in hypertension development.


Assuntos
Pressão Sanguínea , Hipertensão/fisiopatologia , Macrófagos , Animais , Humanos , Fatores de Risco
20.
Nat Commun ; 11(1): 6296, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33293558

RESUMO

Macrophages represent a major immune cell population in atherosclerotic plaques and play central role in the progression of this lipid-driven chronic inflammatory disease. Targeting immunometabolism is proposed as a strategy to revert aberrant macrophage activation to improve disease outcome. Here, we show ATP citrate lyase (Acly) to be activated in inflammatory macrophages and human atherosclerotic plaques. We demonstrate that myeloid Acly deficiency induces a stable plaque phenotype characterized by increased collagen deposition and fibrous cap thickness, along with a smaller necrotic core. In-depth functional, lipidomic, and transcriptional characterization indicate deregulated fatty acid and cholesterol biosynthesis and reduced liver X receptor activation within the macrophages in vitro. This results in macrophages that are more prone to undergo apoptosis, whilst maintaining their capacity to phagocytose apoptotic cells. Together, our results indicate that targeting macrophage metabolism improves atherosclerosis outcome and we reveal Acly as a promising therapeutic target to stabilize atherosclerotic plaques.


Assuntos
ATP Citrato (pro-S)-Liase/deficiência , Macrófagos/metabolismo , Placa Aterosclerótica/imunologia , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , ATP Citrato (pro-S)-Liase/genética , Idoso , Animais , Apoptose/imunologia , Colesterol/biossíntese , Colágeno/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ácidos Graxos/biossíntese , Feminino , Fibrose , Perfilação da Expressão Gênica , Humanos , Lipidômica , Lipogênese/imunologia , Receptores X do Fígado/metabolismo , Ativação de Macrófagos , Macrófagos/imunologia , Masculino , Camundongos Knockout , Necrose/imunologia , Necrose/patologia , Fagocitose , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/patologia
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