Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 43
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Nat Metab ; 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34650273

RESUMO

Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here we reveal that glutaminase-1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis in mice. In addition, impaired macrophage glutaminolysis exacerbates atherosclerosis, a condition during which, efficient apoptotic cell debris clearance is critical to limit disease progression. Glutaminase-1 expression strongly correlates with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling reveals that macrophage efferocytic capacity relies on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase to fuel ɑ-ketoglutarate-dependent immunometabolism. This pathway is necessary to meet the unique requirements of efferocytosis for cellular detoxification and high-energy cytoskeletal rearrangements. Thus, we uncover a role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease in mouse and humans.

2.
Nat Commun ; 12(1): 5255, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489438

RESUMO

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling.


Assuntos
Tecido Adiposo Marrom/citologia , Monócitos/fisiologia , Adiponectina/genética , Tecido Adiposo Marrom/fisiologia , Animais , Diferenciação Celular/genética , Contagem de Leucócitos , Macrófagos/citologia , Macrófagos/fisiologia , Glicoproteínas de Membrana/metabolismo , Camundongos Transgênicos , Monócitos/citologia , Tomografia por Emissão de Pósitrons , Receptores CCR2/genética , Receptores CCR2/metabolismo
3.
Atherosclerosis ; 334: 1-8, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34450556

RESUMO

Metabolism plays a key role in controlling immune cell functions. In this review, we will discuss the diversity of plaque resident myeloid cells and will focus on their metabolic demands that could reflect on their particular intraplaque localization. Defining the metabolic configuration of plaque resident myeloid cells according to their topologic distribution could provide answers to key questions regarding their functions and contribution to disease development.

4.
Nat Commun ; 12(1): 3350, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099721

RESUMO

Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36ΔLEC mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.


Assuntos
Antígenos CD36/genética , Antígenos CD36/metabolismo , Células Endoteliais/metabolismo , Resistência à Insulina/fisiologia , Obesidade Abdominal/metabolismo , Animais , Antígenos CD , Caderinas , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Glucose/metabolismo , Inflamação , Vasos Linfáticos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fosforilação , Transcriptoma , Fator C de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
Infect Immun ; 89(9): e0073420, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-33820816

RESUMO

Along with respiratory tract disease per se, viral respiratory infections can also cause extrapulmonary complications with a potentially critical impact on health. In the present study, we used an experimental model of influenza A virus (IAV) infection to investigate the nature and outcome of the associated gut disorders. In IAV-infected mice, the signs of intestinal injury and inflammation, altered gene expression, and compromised intestinal barrier functions peaked on day 7 postinfection. As a likely result of bacterial component translocation, gene expression of inflammatory markers was upregulated in the liver. These changes occurred concomitantly with an alteration of the composition of the gut microbiota and with a decreased production of the fermentative, gut microbiota-derived products short-chain fatty acids (SCFAs). Gut inflammation and barrier dysfunction during influenza were not attributed to reduced food consumption, which caused in part gut dysbiosis. Treatment of IAV-infected mice with SCFAs was associated with an enhancement of intestinal barrier properties, as assessed by a reduction in the translocation of dextran and a decrease in inflammatory gene expression in the liver. Lastly, SCFA supplementation during influenza tended to reduce the translocation of the enteric pathogen Salmonella enterica serovar Typhimurium and to enhance the survival of doubly infected animals. Collectively, influenza virus infection can remotely impair the gut's barrier properties and trigger secondary enteric infections. The latter phenomenon can be partially countered by SCFA supplementation.


Assuntos
Infecções por Enterobacteriaceae/etiologia , Ácidos Graxos Voláteis/biossíntese , Interações Hospedeiro-Patógeno , Vírus da Influenza A/fisiologia , Influenza Humana/complicações , Influenza Humana/virologia , Mucosa Intestinal/metabolismo , Interações Microbianas , Suscetibilidade a Doenças , Disbiose , Infecções por Enterobacteriaceae/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Influenza Humana/metabolismo , Mucosa Intestinal/imunologia
6.
Blood Adv ; 5(5): 1523-1534, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33683342

RESUMO

Dysregulated immune response is the key factor leading to unfavorable coronavirus disease 2019 (COVID-19) outcome. Depending on the pathogen-associated molecular pattern, the NLRP3 inflammasome can play a crucial role during innate immunity activation. To date, studies describing the NLRP3 response during severe acute respiratory syndrome coronavirus 2 infection in patients are lacking. We prospectively monitored caspase-1 activation levels in peripheral myeloid cells from healthy donors and patients with mild to critical COVID-19. The caspase-1 activation potential in response to NLRP3 inflammasome stimulation was opposed between nonclassical monocytes and CD66b+CD16dim granulocytes in severe and critical COVID-19 patients. Unexpectedly, the CD66b+CD16dim granulocytes had decreased nigericin-triggered caspase-1 activation potential associated with an increased percentage of NLRP3 inflammasome impaired immature neutrophils and a loss of eosinophils in the blood. In patients who recovered from COVID-19, nigericin-triggered caspase-1 activation potential in CD66b+CD16dim cells was restored and the proportion of immature neutrophils was similar to control. Here, we reveal that NLRP3 inflammasome activation potential differs among myeloid cells and could be used as a biomarker of a COVID-19 patient's evolution. This assay could be a useful tool to predict patient outcome. This trial was registered at www.clinicaltrials.gov as #NCT04385017.


Assuntos
COVID-19/sangue , Inflamassomos/metabolismo , Células Mieloides/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Biomarcadores/sangue , COVID-19/imunologia , Estudos de Casos e Controles , Humanos , Inflamassomos/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação
7.
J Vis Exp ; (165)2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33283786

RESUMO

Lymphatic collecting vessels and lymph nodes are inevitably embedded in adipose tissue. The physiological significance of this observation remains still not elucidated. However, obesity is characterized by impaired lymphatic function and increased vessel permeability. Inversely, lymphatic dysfunction induces obesity in mice, suggesting a significant interplay between lymphatic vessels and the adipose tissue. Therefore, understanding factors leading to lymphatic dysfunction might open new therapeutic windows to prevent obesity and associated comorbidities. The first step in this process requires a precise and detailed visualization of the lymphatic network in healthy and inflamed adipose tissue. Here, we describe a rapid, inexpensive, and efficient method that allows to label and analyze lymphatic and blood vessels. This approach takes advantage of the skin-draining brachial lymph node localization within the subcutaneous adipose tissue. The lymphatic arborization of this tissue can be revealed by injecting fluorochrome-conjugated lectins subcutaneously. Moreover, the in vivo labeling approach provides a way to evaluate lymphatic vessel density and functions. Coupled to blood vessel, adipocyte and immune cell staining, the protocol allows for high-resolution mapping of the subcutaneous adipose tissue by 3D imaging.


Assuntos
Vasos Sanguíneos/patologia , Vasos Linfáticos/patologia , Obesidade/sangue , Obesidade/patologia , Animais , Linfonodos/patologia , Camundongos Endogâmicos C57BL , Coloração e Rotulagem , Gordura Subcutânea/irrigação sanguínea
8.
Cells ; 10(1)2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374145

RESUMO

Atherosclerotic lesions progress through the continued recruitment of circulating blood monocytes that differentiate into macrophages within plaque. Lesion-associated macrophages are the primary immune cells present in plaque, where they take up cholesterol and store lipids in the form of small droplets resulting in a unique morphology termed foam cell. Recent scientific advances have used single-cell gene expression profiling, live-cell imaging, and fate mapping approaches to describe macrophage and monocyte contributions to pro- or anti-inflammatory mechanisms, in addition to functions of motility and proliferation within lesions. Yet, many questions regarding tissue-specific regulation of monocyte-to-macrophage differentiation and the contribution of recruited monocytes at stages of atherosclerotic disease progression remain unknown. In this review, we highlight recent advances regarding the role of monocyte and macrophage dynamics in atherosclerotic disease and identify gaps in knowledge that we hope will allow for advancing therapeutic treatment or prevention strategies for cardiovascular disease.


Assuntos
Aterosclerose/metabolismo , Células Espumosas/metabolismo , Monócitos/metabolismo , Placa Aterosclerótica/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Citocinas/metabolismo , Células Espumosas/citologia , Humanos , Camundongos , Monócitos/patologia
9.
J Vis Exp ; (162)2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32894273

RESUMO

Obesity is a major worldwide public health issue that increases the risk to develop cardiovascular diseases, type-2 diabetes, and liver diseases. Obesity is characterized by an increase in adipose tissue (AT) mass due to adipocyte hyperplasia and/or hypertrophia, leading to profound remodeling of its three-dimensional structure. Indeed, the maximal capacity of AT to expand during obesity is pivotal to the development of obesity-associated pathologies. This AT expansion is an important homeostatic mechanism to enable adaptation to an excess of energy intake and to avoid deleterious lipid spillover to other metabolic organs, such as muscle and liver. Therefore, understanding the structural remodeling that leads to the failure of AT expansion is a fundamental question with high clinical applicability. In this article, we describe a simple and fast clearing method that is routinely used in our laboratory to explore the morphology of mouse and human white adipose tissue by fluorescent imaging. This optimized AT clearing method is easily performed in any standard laboratory equipped with a chemical hood, a temperature-controlled orbital shaker and a fluorescent microscope. Moreover, the chemical compounds used are readily available. Importantly, this method allows one to resolve the 3D AT structure by staining various markers to specifically visualize the adipocytes, the neuronal and vascular networks, and the innate and adaptive immune cells distribution.


Assuntos
Tecido Adiposo/patologia , Imageamento Tridimensional , Salicilatos/farmacocinética , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Humanos , Camundongos , Microscopia de Fluorescência , Obesidade/metabolismo , Obesidade/patologia
10.
Nat Immunol ; 21(10): 1194-1204, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32895539

RESUMO

Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DCs) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stages of disease is unknown. Using murine lineage-tracing models and gene expression profiling, we reveal that myeloid cells present in the intima of the aortic arch are not DCs but instead specialized aortic intima resident macrophages (MacAIR) that depend upon colony-stimulating factor 1 and are sustained by local proliferation. Although MacAIR comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaques is overtaken by recruited monocytes, which induce MacAIR-defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.


Assuntos
Aorta/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Placa Aterosclerótica/imunologia , Túnica Íntima/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Movimento Celular , Proliferação de Células , Células Cultivadas , Colesterol/metabolismo , Progressão da Doença , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parabiose , Fagocitose
11.
J Lipid Atheroscler ; 9(2): 231-242, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32821733

RESUMO

Hypercholesterolemia contributes to the chronic inflammatory response during the progression of atherosclerosis, in part by favoring cholesterol loading in macrophages and other immune cells. However, macrophages encounter a substantial amount of other lipids and nutrients after ingesting atherogenic lipoprotein particles or clearing apoptotic cells, increasing their metabolic load and impacting their behavior during atherosclerosis plaque progression. This review examines whether and how fatty acids and glucose shape the cellular metabolic reprogramming of macrophages in atherosclerosis to modulate the onset phase of inflammation and the later resolution stage, in which the balance is tipped toward tissue repair.

12.
Cell Rep ; 30(10): 3397-3410.e5, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32160545

RESUMO

Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rß signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transtornos Mieloproliferativos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/deficiência , Transportador 1 de Cassete de Ligação de ATP/genética , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/patologia , Colesterol/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Interleucina-3/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Lipoproteínas HDL/metabolismo , Mutação com Perda de Função/genética , Camundongos , Camundongos Endogâmicos C57BL , Mielopoese , Transtornos Mieloproliferativos/patologia , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Esplenomegalia/patologia
13.
Eur J Immunol ; 49(11): 2012-2018, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31251389

RESUMO

Macrophages play a central role during infection, inflammation and tissue homeostasis maintenance. Macrophages have been identified in all organs and their core transcriptomic signature and functions differ from one tissue to another. Interestingly, macrophages have also been identified in the peritoneal cavity and these cells have been extensively used as a model for phagocytosis, efferocytosis and polarization. Peritoneal macrophages are involved in B-cell IgA production, control of inflammation and wound healing following thermal-induced liver surface injury. These cells presumably require and interact with the omentum, where milky spot stromal cells have been proposed to secrete CSF1 (colony stimulating factor 1). Peritoneal macrophages depend on CSF1 for their generation and survival, but the identity of CSF1 producing cells inside the large peritoneal cavity remains unknown. Here we investigated peritoneal macrophage localization and their interaction with mesothelial cells, the major cell type predicted to secrete CSF1. Our data revealed that mesothelial cells produce membrane bound and secreted CSF1 that both sustain peritoneal macrophage growth.


Assuntos
Células Epiteliais/metabolismo , Epitélio/metabolismo , Fator Estimulador de Colônias de Macrófagos/genética , Macrófagos Peritoneais/metabolismo , Células Estromais/metabolismo , Animais , Comunicação Celular/genética , Comunicação Celular/imunologia , Membrana Celular/imunologia , Membrana Celular/metabolismo , Sobrevivência Celular , Técnicas de Cocultura , Células Epiteliais/citologia , Células Epiteliais/imunologia , Epitélio/imunologia , Espaço Extracelular/imunologia , Espaço Extracelular/metabolismo , Expressão Gênica , Fator Estimulador de Colônias de Macrófagos/imunologia , Macrófagos Peritoneais/citologia , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Transgênicos , Cavidade Peritoneal/citologia , Transdução de Sinais , Células Estromais/citologia , Células Estromais/imunologia
14.
Cell Rep ; 25(12): 3329-3341.e5, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30566860

RESUMO

Obesity modifies T cell populations in adipose tissue, thereby contributing to adipose tissue inflammation and insulin resistance. Here, we show that Rab4b, a small GTPase governing endocytic trafficking, is pivotal in T cells for the development of these pathological events. Rab4b expression is decreased in adipose T cells from mice and patients with obesity. The specific depletion of Rab4b in T cells causes adipocyte hypertrophy and insulin resistance in chow-fed mice and worsens insulin resistance in obese mice. This phenotype is driven by an increase in adipose Th17 and a decrease in adipose Treg due to a cell-autonomous skew of differentiation toward Th17. The Th17/Treg imbalance initiates adipose tissue inflammation and reduces adipogenesis, leading to lipid deposition in liver and muscles. Therefore, we propose that the obesity-induced loss of Rab4b in adipose T cells may contribute to maladaptive white adipose tissue remodeling and insulin resistance by altering adipose T cell fate.


Assuntos
Tecido Adiposo/fisiopatologia , Resistência à Insulina , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Proteínas rab4 de Ligação ao GTP/deficiência , Adipócitos/metabolismo , Tecido Adiposo/patologia , Envelhecimento/patologia , Animais , Complexo CD3/metabolismo , Polaridade Celular , Ácidos Graxos/sangue , Intolerância à Glucose/complicações , Humanos , Inflamação/patologia , Metabolismo dos Lipídeos , Camundongos Knockout , Obesidade/sangue , Obesidade/complicações , Obesidade/imunologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas rab4 de Ligação ao GTP/genética , Proteínas rab4 de Ligação ao GTP/metabolismo
15.
Circ Res ; 122(10): 1369-1384, 2018 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-29523554

RESUMO

RATIONALE: Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. OBJECTIVE: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. METHODS AND RESULTS: We show that LIPA inhibition causes a defective efferocytic response because of impaired generation of 25-hydroxycholesterol and 27-hydroxycholesterol. Reduced synthesis of 25-hydroxycholesterol after LIPA inhibition contributed to defective mitochondria-associated membrane leading to mitochondrial oxidative stress-induced NLRP3 (NOD-like receptor family, pyrin domain containing) inflammasome activation and caspase-1-dependent Rac1 (Ras-related C3 botulinum toxin substrate 1) degradation. A secondary event consisting of failure to appropriately activate liver X receptor-mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. CONCLUSIONS: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.


Assuntos
Colesterol/metabolismo , Inflamação/metabolismo , Lisossomos/metabolismo , Macrófagos/metabolismo , Oxisteróis/metabolismo , Esterol Esterase/metabolismo , Animais , Apoptose , Transporte Biológico , Ésteres do Colesterol/metabolismo , Eritrócitos/metabolismo , Hidrólise , Hipercolesterolemia/metabolismo , Inflamassomos/metabolismo , Receptores X do Fígado/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuropeptídeos/metabolismo , Receptores de LDL/metabolismo , Esplenomegalia/metabolismo , Esterol Esterase/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/metabolismo
16.
Atherosclerosis ; 271: 102-110, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29482037

RESUMO

The increasing incidence of obesity and its socio-economical impact is a global health issue due to its associated co-morbidities, namely diabetes and cardiovascular disease [1-5]. Obesity is characterized by an increase in adipose tissue, which promotes the recruitment of immune cells resulting in low-grade inflammation and dysfunctional metabolism. Macrophages are the most abundant immune cells in the adipose tissue of mice and humans. The adipose tissue also contains other myeloid cells (dendritic cells (DC) and neutrophils) and to a lesser extent lymphocyte populations, including T cells, B cells, Natural Killer (NK) and Natural Killer T (NKT) cells. While the majority of studies have linked adipose tissue macrophages (ATM) to the development of low-grade inflammation and co-morbidities associated with obesity, emerging evidence suggests for a role of other immune cells within the adipose tissue that may act in part by supporting macrophage homeostasis. In this review, we summarize the current knowledge of the functions ATMs, DCs and B cells possess during steady-state and obesity.


Assuntos
Tecido Adiposo/imunologia , Linfócitos B/imunologia , Células Dendríticas/imunologia , Macrófagos/imunologia , Obesidade/imunologia , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Adiposidade , Animais , Linfócitos B/metabolismo , Comunicação Celular , Citocinas/metabolismo , Células Dendríticas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Fenótipo , Transdução de Sinais
17.
Mediators Inflamm ; 2018: 2426138, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30647530

RESUMO

Monocyte and macrophage diversity is evidenced by the modulation of cell surface markers and differential production of soluble mediators. These immune cells play key roles in controlling tissue homeostasis, infections, and excessive inflammation. Macrophages remove dead cells in a process named efferocytosis, contributing to the healthy tissue maintenance. Recently, it became clear that the main macrophage functions are under metabolic control. Modulation of glucose, fatty acid, and amino acid metabolism is associated with various macrophage activations in response to external stimuli. Deciphering these metabolic pathways provided critical information about macrophage functions.


Assuntos
Ativação de Macrófagos/fisiologia , Macrófagos/metabolismo , Aminoácidos/metabolismo , Animais , Ácidos Graxos/metabolismo , Glucose/metabolismo , Humanos , Fagocitose/fisiologia
18.
Circ Res ; 121(6): 662-676, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28696252

RESUMO

RATIONALE: Ambient temperature is a risk factor for cardiovascular disease. Cold weather increases cardiovascular events, but paradoxically, cold exposure is metabolically protective because of UCP1 (uncoupling protein 1)-dependent thermogenesis. OBJECTIVE: We sought to determine the differential effects of ambient environmental temperature challenge and UCP1 activation in relation to cardiovascular disease progression. METHODS AND RESULTS: Using mouse models of atherosclerosis housed at 3 different ambient temperatures, we observed that cold temperature enhanced, whereas thermoneutral housing temperature inhibited atherosclerotic plaque growth, as did deficiency in UCP1. However, whereas UCP1 deficiency promoted poor glucose tolerance, thermoneutral housing enhanced glucose tolerance, and this effect held even in the context of UCP1 deficiency. In conditions of thermoneutrality, but not UCP1 deficiency, circulating monocyte counts were reduced, likely accounting for fewer monocytes entering plaques. Reductions in circulating blood monocytes were also found in a large human cohort in correlation with environmental temperature. By contrast, reduced plaque growth in mice lacking UCP1 was linked to lower cholesterol. Through application of a positron emission tomographic tracer to track CCR2+ cell localization and intravital 2-photon imaging of bone marrow, we associated thermoneutrality with an increased monocyte retention in bone marrow. Pharmacological activation of ß3-adrenergic receptors applied to mice housed at thermoneutrality induced UCP1 in beige fat pads but failed to promote monocyte egress from the marrow. CONCLUSIONS: Warm ambient temperature is, like UCP1 deficiency, atheroprotective, but the mechanisms of action differ. Thermoneutrality associates with reduced monocyte egress from the bone marrow in a UCP1-dependent manner in mice and likewise may also suppress blood monocyte counts in man.


Assuntos
Aterosclerose/metabolismo , Monócitos/fisiologia , Termogênese , Proteína Desacopladora 1/genética , Animais , Aterosclerose/sangue , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Movimento Celular , Colesterol/metabolismo , Temperatura Baixa , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Placa Aterosclerótica/sangue , Placa Aterosclerótica/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/metabolismo
19.
Pflugers Arch ; 469(3-4): 465-472, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28220247

RESUMO

The maintenance of tissue homeostasis is indispensable for health. In particular, removal of toxic compounds from cells and organs is a vital process for the organism. The lymphatic vasculature works in order to ensure the efficient removal of tissue waste. Forbidden over the last decade when more attention was paid to the blood vasculature, studies on the lymphatic vasculature have gained momentum during the last couple of years. The lymphatic vasculature naturally runs parallel to the blood vasculature and their synergistic work is critical for maintaining tissue homeostasis. Diminished lymphatic function results in accumulation of body fluids in tissues and gives rise to edema. Recently, it became obvious that immune cells including myeloid cells and lymphocytes are able to interact with and control the development and function of the lymphatic vasculature. In this review, we will focus on the interaction between myeloid cells, including macrophages, monocytes, and dendritic cells, with lymphatic vessels.


Assuntos
Sistema Linfático/fisiologia , Células Mieloides/fisiologia , Animais , Células Endoteliais/fisiologia , Homeostase/fisiologia , Humanos , Vasos Linfáticos/fisiologia , Linfócitos/fisiologia , Macrófagos/fisiologia
20.
Cell Mol Gastroenterol Hepatol ; 3(1): 82-98, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28066800

RESUMO

BACKGROUND & AIMS: CD36 has immuno-metabolic actions and is abundant in the small intestine on epithelial, endothelial and immune cells. We examined the role of CD36 in gut homeostasis using mice null for CD36 (CD36KO) and with CD36 deletion specific to enterocytes (Ent-CD36KO) or endothelial cells (EC-CD36KO). METHODS: Intestinal morphology was evaluated using immunohistochemistry and electron microscopy (EM). Intestinal inflammation was determined from neutrophil infiltration and expression of cytokines, toll-like receptors and COX-2. Barrier integrity was assessed from circulating lipopolysaccharide (LPS) and dextran administered intragastrically. Epithelial permeability to luminal dextran was visualized using two photon microscopy. RESULTS: The small intestines of CD36KO mice fed a chow diet showed several abnormalities including extracellular matrix (ECM) accumulation with increased expression of ECM proteins, evidence of neutrophil infiltration, inflammation and compromised barrier function. EM showed shortened desmosomes with decreased desmocollin 2 expression. Systemically, leukocytosis and neutrophilia were present together with 80% reduction of anti-inflammatory Ly6Clow monocytes. Bone marrow transplants supported the primary contribution of non-hematopoietic cells to the inflammatory phenotype. Specific deletion of endothelial but not of enterocyte CD36 reproduced many of the gut phenotypes of germline CD36KO mice including fibronectin deposition, increased interleukin 6, neutrophil infiltration, desmosome shortening and impaired epithelial barrier function. CONCLUSIONS: CD36 loss results in chronic neutrophil infiltration of the gut, impairs barrier integrity and systemically causes subclinical inflammation. Endothelial cell CD36 deletion reproduces the major intestinal phenotypes. The findings suggest an important role of the endothelium in etiology of gut inflammation and loss of epithelial barrier integrity.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...