Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Nat Immunol ; 20(9): 1186-1195, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31384058

RESUMO

Macrophages are activated during microbial infection to coordinate inflammatory responses and host defense. Here we find that in macrophages activated by bacterial lipopolysaccharide (LPS), mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulates glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle, boosts glucose oxidation to fuel the production of acetyl coenzyme A, acetylation of histones and induction of genes encoding inflammatory mediators. While acute exposure to LPS drives macrophage activation, prolonged exposure to LPS triggers tolerance to LPS, where macrophages induce immunosuppression to limit the detrimental effects of sustained inflammation. The shift in the inflammatory response is modulated by GPD2, which coordinates a shutdown of oxidative metabolism; this limits the availability of acetyl coenzyme A for histone acetylation at genes encoding inflammatory mediators and thus contributes to the suppression of inflammatory responses. Therefore, GPD2 and the glycerol phosphate shuttle integrate the extent of microbial stimulation with glucose oxidation to balance the beneficial and detrimental effects of the inflammatory response.


Assuntos
Glucose/metabolismo , Glicerolfosfato Desidrogenase/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Acetilcoenzima A/biossíntese , Acetilação , Animais , Feminino , Histonas/metabolismo , Inflamação/patologia , Lipopolissacarídeos , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução
3.
Semin Immunol ; 27(4): 286-96, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26360589

RESUMO

Macrophages are pleiotropic cells that assume a variety of functions depending on their tissue of residence and tissue state. They maintain homeostasis as well as coordinate responses to stresses such as infection and metabolic challenge. The ability of macrophages to acquire diverse, context-dependent activities requires their activation (or polarization) to distinct functional states. While macrophage activation is well understood at the level of signal transduction and transcriptional regulation, the metabolic underpinnings are poorly understood. Importantly, emerging studies indicate that metabolic shifts play a pivotal role in control of macrophage activation and acquisition of context-dependent effector activities. The signals that drive macrophage activation impinge on metabolic pathways, allowing for coordinate control of macrophage activation and metabolism. Here we discuss how mTOR and Akt, major metabolic regulators and targets of such activation signals, control macrophage metabolism and activation. Dysregulated macrophage activities contribute to many diseases, including infectious, inflammatory, and metabolic diseases and cancer, thus a better understanding of metabolic control of macrophage activation could pave the way to the development of new therapeutic strategies.


Assuntos
Ativação de Macrófagos , Macrófagos/metabolismo , Transdução de Sinais , Animais , Glutamina/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
4.
Mediators Inflamm ; 2015: 436017, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25944983

RESUMO

Inflammatory bowel disease (IBD) including Crohn's disease and ulcerative colitis is often precipitated by an abnormal immune response to microbiota due to host genetic aberrancies. Recent studies highlight the importance of the host genome and microflora interactions in the pathogenesis of mucosal inflammation including IBD. Specifically, genome-wide (GWAS) and also next-generation sequencing (NGS)-including whole exome or genome sequencing-have uncovered a large number of susceptibility loci that predispose to autoimmune diseases and/or the two phenotypes of IBD. In addition, the generation of "IBD-prone" animal models using both reverse and forward genetic approaches has not only helped confirm the identification of susceptibility loci but also shed critical insight into the underlying molecular and cellular pathways that drive colitis development. In this review, we summarize recent findings derived from studies involving a novel early-onset model of colitis as it develops in GTPase of immunity-associated protein 5- (Gimap5-) deficient mice. In humans, GIMAP5 has been associated with autoimmune diseases although its function is poorly defined. Here, we discuss how defects in Gimap5 function impair immunological tolerance and lymphocyte survival and ultimately drive the development of CD4(+) T cell-mediated early-onset colitis.


Assuntos
GTP Fosfo-Hidrolases/fisiologia , Proteínas de Ligação ao GTP/fisiologia , Intestinos/imunologia , Tolerância Periférica , Linfócitos T/citologia , Animais , Colite Ulcerativa/imunologia , Doença de Crohn/imunologia , GTP Fosfo-Hidrolases/genética , Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Guanosina Trifosfato/química , Homeostase , Humanos , Imunidade , Doenças Inflamatórias Intestinais/imunologia , Camundongos , Camundongos Transgênicos , Fenótipo , Ratos
5.
J Immunol ; 188(1): 146-54, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22106000

RESUMO

Previously, we reported the abrogation of quiescence and reduced survival in lymphocytes from Gimap5(sph/sph) mice, an ENU germline mutant with a missense mutation in the GTPase of immunity-associated protein 5 (Gimap5). These mice showed a progressive loss of peripheral lymphocyte populations and developed spontaneous colitis, resulting in early mortality. In this study, we identify the molecular pathways that contribute to the onset of colitis in Gimap5(sph/sph) mice. We show that CD4(+) T cells become Th1/Th17 polarized and are critically important for the development of colitis. Concomitantly, regulatory T cells become reduced in frequency in the peripheral tissues, and their immunosuppressive capacity becomes impaired. Most importantly, these progressive changes in CD4(+) T cells are associated with the loss of Forkheadbox group O (Foxo)1, Foxo3, and Foxo4 expression. Our data establish a novel link between Gimap5 and Foxo expression and provide evidence for a regulatory mechanism that controls Foxo protein expression and may help to maintain immunological tolerance.


Assuntos
Fatores de Transcrição Forkhead/imunologia , GTP Fosfo-Hidrolases/imunologia , Regulação da Expressão Gênica/imunologia , Tolerância Imunológica/fisiologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Colite/genética , Colite/imunologia , Colite/metabolismo , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Proteínas de Ligação ao GTP , Camundongos , Camundongos Knockout , Mutação de Sentido Incorreto , Linfócitos T Auxiliares-Indutores/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...