RESUMEN
Diabetes is known to increase susceptibility to respiratory infections, but the underlying basis remains elusive. In a recent study in Nature, Nobs et al. showed that hyperglycemia impinges on the histone acetylation landscape to impair the ability of lung dendritic cells to prime adaptive immunity.
Asunto(s)
Pulmón , Azúcares , Humanos , Inmunidad Adaptativa , Células DendríticasRESUMEN
Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and comprises primordial innate defense. Phagocytes mobilize interferon-inducible responses upon engagement of well-characterized signaling pathways by pathogen-associated molecular patterns (PAMPs). The signals controlling deployment of constitutive cell-autonomous responses during infection have remained elusive. Vita-PAMPs denote microbial viability, signaling the danger of cellular exploitation by intracellular pathogens. We show that cyclic-di-adenosine monophosphate in live Gram-positive bacteria is a vita-PAMP, engaging the innate sensor stimulator of interferon genes (STING) to mediate endoplasmic reticulum (ER) stress. Subsequent inactivation of the mechanistic target of rapamycin mobilizes autophagy, which sequesters stressed ER membranes, resolves ER stress, and curtails phagocyte death. This vita-PAMP-induced ER-phagy additionally orchestrates an interferon response by localizing ER-resident STING to autophagosomes. Our findings identify stress-mediated ER-phagy as a cell-autonomous response mobilized by STING-dependent sensing of a specific vita-PAMP and elucidate how innate receptors engage multilayered homeostatic mechanisms to promote immunity and survival after infection.
Asunto(s)
Bacterias Grampositivas/fisiología , Infecciones por Bacterias Grampositivas/inmunología , Proteínas de la Membrana/metabolismo , Fagocitos/inmunología , Animales , Autofagia , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico , Femenino , Masculino , Ratones , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
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.
Asunto(s)
Glucosa/metabolismo , Glicerolfosfato Deshidrogenasa/metabolismo , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Acetilcoenzima A/biosíntesis , Acetilación , Animales , Femenino , Histonas/metabolismo , Inflamación/patología , Lipopolisacáridos , Macrófagos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-ReducciónRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
To celebrate our Focus Issue, we asked a selection of researchers working on different aspects of metabolism what they are excited about and what is still to come. They discuss emerging concepts, unanswered questions, things to consider, and technologies that are enabling new discoveries, as well as developing and integrating approaches to drive the field forward.
Asunto(s)
Metabolismo/fisiología , Investigación/tendencias , Humanos , InvestigadoresRESUMEN
Most inducible transcriptional programs consist of primary and secondary response genes (PRGs and SRGs) that differ in their kinetics of expression and in their requirements for new protein synthesis and chromatin remodeling. Here we show that many PRGs, in contrast to SRGs, have preassembled RNA polymerase II (Pol II) and positive histone modifications at their promoters in the basal state. Pol II at PRGs generates low levels of full-length unspliced transcripts but fails to make mature, protein-coding transcripts in the absence of stimulation. Induction of PRGs is controlled at the level of transcriptional elongation and mRNA processing, through the signal-dependent recruitment of P-TEFb. P-TEFb is in turn recruited by the bromodomain-containing protein Brd4, which detects H4K5/8/12Ac inducibly acquired at PRG promoters. Our findings suggest that the permissive structure of PRGs both stipulates their unique regulation in the basal state by corepressor complexes and enables their rapid induction in multiple cell types.
Asunto(s)
Ensamble y Desensamble de Cromatina , Secuencias Reguladoras de Ácidos Nucleicos , Activación Transcripcional , Animales , Línea Celular , Código de Histonas , Histonas/metabolismo , Humanos , Lipopolisacáridos/inmunología , Lipopolisacáridos/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Fosforilación , Estructura Terciaria de Proteína , ARN Polimerasa II/química , ARN Polimerasa II/metabolismoRESUMEN
Mitochondria are critical for regulation of the activation, differentiation, and survival of macrophages and other immune cells. In response to various extracellular signals, such as microbial or viral infection, changes to mitochondrial metabolism and physiology could underlie the corresponding state of macrophage activation. These changes include alterations of oxidative metabolism, mitochondrial membrane potential, and tricarboxylic acid (TCA) cycling, as well as the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA) and transformation of the mitochondrial ultrastructure. Here, we provide an updated review of how changes in mitochondrial metabolism and various metabolites such as fumarate, succinate, and itaconate coordinate to guide macrophage activation to distinct cellular states, thus clarifying the vital link between mitochondria metabolism and immunity. We also discuss how in disease settings, mitochondrial dysfunction and oxidative stress contribute to dysregulation of the inflammatory response. Therefore, mitochondria are a vital source of dynamic signals that regulate macrophage biology to fine-tune immune responses.
Asunto(s)
Activación de Macrófagos , Macrófagos/metabolismo , Mitocondrias/metabolismo , Animales , Humanos , Estrés OxidativoRESUMEN
AIMS: Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance. METHODS AND RESULTS: We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe-/- mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD. CONCLUSION: Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α-CREB-OGDH axis in macrophages.
Asunto(s)
Aneurisma de la Aorta , Animales , Biomarcadores , Disección , Humanos , Metabolómica , Ratones , Ácido SuccínicoRESUMEN
Toll-like receptor 4 (TLR4) induces two distinct signaling pathways controlled by the TIRAP-MyD88 and TRAM-TRIF pairs of adaptor proteins, which elicit the production of proinflammatory cytokines and type I interferons, respectively. How TLR4 coordinates the activation of these two pathways is unknown. Here we show that TLR4 activated these two signaling pathways sequentially in a process organized around endocytosis of the TLR4 complex. We propose that TLR4 first induces TIRAP-MyD88 signaling at the plasma membrane and is then endocytosed and activates TRAM-TRIF signaling from early endosomes. Our data emphasize a unifying theme in innate immune recognition whereby all type I interferon-inducing receptors signal from an intracellular location.
Asunto(s)
Endocitosis/fisiología , Interferón beta/biosíntesis , Glicoproteínas de Membrana/fisiología , Proteínas de Transporte de Membrana/fisiología , Transducción de Señal/inmunología , Receptor Toll-Like 4/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/fisiología , Secuencias de Aminoácidos/inmunología , Secuencia de Aminoácidos , Animales , Línea Celular , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Endocitosis/genética , Humanos , Líquido Intracelular/inmunología , Líquido Intracelular/metabolismo , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/fisiología , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-1/fisiología , Transducción de Señal/genética , Receptor Toll-Like 4/antagonistas & inhibidores , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/fisiologíaRESUMEN
The effector functions of natural killer cells are regulated by activating receptors, which recognize stress-inducible ligands expressed on target cells and signal through association with signaling adaptors. Here we developed a mouse model in which a fusion of the signaling adaptor DAP10 and ubiquitin efficiently downregulated expression of the activating receptor NKG2D on the surfaces of natural killer cells. With this system, we identified coupling of the signaling pathways triggered by NKG2D and DAP10 to those initiated by the interleukin 15 receptor. We suggest that this coupling of activating receptors to other receptor systems could function more generally to regulate cell type-specific signaling events in distinct physiological contexts.
Asunto(s)
Células Asesinas Naturales/fisiología , Proteínas de la Membrana/fisiología , Receptores Inmunológicos/fisiología , Receptores de Interleucina-15/fisiología , Transducción de Señal , Animales , Proteínas de la Membrana/metabolismo , Ratones , Modelos Animales , Modelos Biológicos , Subfamilia K de Receptores Similares a Lectina de Células NK , Receptores Inmunológicos/química , Receptores Inmunológicos/metabolismo , Receptores de Interleucina-15/metabolismo , Receptores de Células Asesinas NaturalesRESUMEN
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.
Asunto(s)
Activación de Macrófagos , Macrófagos/metabolismo , Transducción de Señal , Animales , Glutamina/metabolismo , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The ability of a primary challenge to protect against secondary infection (e.g., during vaccination) independent of the adaptive immune system is mediated in part by macrophage 'training'. Two new studies show that macrophage training is associated with genome-wide epigenetic changes and is regulated by the mTOR pathway and metabolic reprogramming.
Asunto(s)
Macrófagos/inmunología , Macrófagos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Epigénesis Genética , Humanos , Transducción de SeñalRESUMEN
The NLRP3 inflammasome is a cytosolic complex that activates Caspase-1, leading to maturation of interleukin-1ß (IL-1ß) and IL-18 and induction of proinflammatory cell death in sentinel cells of the innate immune system. Diverse stimuli have been shown to activate the NLRP3 inflammasome during infection and metabolic diseases, implicating the pathway in triggering both adaptive and maladaptive inflammation in various clinically important settings. Here I discuss the emerging model that signals associated with mitochondrial destabilization may critically activate the NLRP3 inflammasome. Together with studies indicating an important role for Ca2+ signaling, these findings suggest that many stimuli engage Ca2+ signaling as an intermediate step to trigger mitochondrial destabilization, generating the mitochondrion-associated ligands that activate the NLRP3 inflammasome.
Asunto(s)
Señalización del Calcio , Inflamasomas/metabolismo , Mitocondrias/metabolismo , Animales , Apoptosis , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Humanos , Inflamasomas/genéticaRESUMEN
Inflammasomes are intracellular sensors that couple detection of pathogens and cellular stress to activation of Caspase-1, and consequent IL-1ß and IL-18 maturation and pyroptotic cell death. Here, we show that the absent in melanoma 2 (AIM2) and nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasomes trigger Caspase-1-dependent mitochondrial damage. Caspase-1 activates multiple pathways to precipitate mitochondrial disassembly, resulting in mitochondrial reactive oxygen species (ROS) production, dissipation of mitochondrial membrane potential, mitochondrial permeabilization, and fragmentation of the mitochondrial network. Moreover, Caspase-1 inhibits mitophagy to amplify mitochondrial damage, mediated in part by cleavage of the key mitophagy regulator Parkin. In the absence of Parkin activity, increased mitochondrial damage augments pyroptosis, as indicated by enhanced plasma membrane permeabilization and release of danger-associated molecular patterns (DAMPs). Therefore, like other initiator caspases, Caspase-1 activation by inflammasomes results in mitochondrial damage.
Asunto(s)
Caspasa 1/metabolismo , Inflamasomas/metabolismo , Mitocondrias/patología , Mitofagia , Animales , Apoptosis , Proteínas Portadoras/metabolismo , Síndromes Periódicos Asociados a Criopirina/enzimología , Síndromes Periódicos Asociados a Criopirina/patología , Proteínas de Unión al ADN/metabolismo , Humanos , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Permeabilidad , Transducción de Señal , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome mediates production of inflammatory mediators, such as IL-1ß and IL-18, and as such is implicated in a variety of inflammatory processes, including infection, sepsis, autoinflammatory diseases, and metabolic diseases. The proximal steps in NLRP3 inflammasome activation are not well understood. Here we elucidate a critical role for Ca(2+) mobilization in activation of the NLRP3 inflammasome by multiple stimuli. We demonstrate that blocking Ca(2+) mobilization inhibits assembly and activation of the NLRP3 inflammasome complex, and that during ATP stimulation Ca(2+) signaling is pivotal in promoting mitochondrial damage. C/EPB homologous protein, a transcription factor that can modulate Ca(2+) release from the endoplasmic reticulum, amplifies NLRP3 inflammasome activation, thus linking endoplasmic reticulum stress to activation of the NLRP3 inflammasome. Our findings support a model for NLRP3 inflammasome activation by Ca(2+)-mediated mitochondrial damage.
Asunto(s)
Calcio/metabolismo , Proteínas Portadoras/metabolismo , Inflamasomas/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Retículo Endoplásmico/metabolismo , Citometría de Flujo/métodos , Inmunidad Innata , Inflamación/metabolismo , Ratones , Ratones Transgénicos , Mitocondrias/metabolismo , Modelos Biológicos , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de SeñalRESUMEN
THEMIS plays an indispensable role in T cells, but its mechanism of action has remained highly controversial. Using the systematic proximity labeling methodology PEPSI, we identify THEMIS as an uncharacterized substrate for the phosphatase SHP1. Saturated mutagenesis assays and mass spectrometry analysis reveal that phosphorylation of THEMIS at the evolutionally conserved Tyr34 residue is oppositely regulated by SHP1 and the kinase LCK. Similar to THEMIS-/- mice, THEMISY34F/Y34F knock-in mice show a significant decrease in CD4 thymocytes and mature CD4 T cells, but display normal thymic development and peripheral homeostasis of CD8 T cells. Mechanistically, the Tyr34 motif in THEMIS, when phosphorylated upon T cell antigen receptor activation, appears to act as an allosteric regulator, binding and stabilizing SHP1 in its active conformation, thus ensuring appropriate negative regulation of T cell antigen receptor signaling. However, cytokine signaling in CD8 T cells fails to elicit THEMIS Tyr34 phosphorylation, indicating both Tyr34 phosphorylation-dependent and phosphorylation-independent roles of THEMIS in controlling T cell maturation and expansion.
Asunto(s)
Péptidos y Proteínas de Señalización Intercelular , Timocitos , Ratones , Animales , Ratones Noqueados , Timocitos/metabolismo , Receptores de Antígenos de Linfocitos T , Transducción de SeñalRESUMEN
Metastasis is the leading cause of high ovarian-cancer-related mortality worldwide. Three major processes constitute the whole metastatic cascade: invasion, intravasation, and extravasation. Tumor cells often reprogram their metabolism to gain advantages in proliferation and survival. However, whether and how those metabolic alterations contribute to the invasiveness of tumor cells has yet to be fully understood. Here we performed a genome-wide CRISPR-Cas9 screening to identify genes participating in tumor cell dissemination and revealed that PTGES3 acts as an invasion suppressor in ovarian cancer. Mechanistically, PTGES3 binds to phosphofructokinase, liver type (PFKL) and generates a local source of prostaglandin E2 (PGE2) to allosterically inhibit the enzymatic activity of PFKL. Repressed PFKL leads to downgraded glycolysis and the subsequent TCA cycle for glucose metabolism. However, ovarian cancer suppresses the expression of PTGES3 and disrupts the PTGES3-PGE2-PFKL inhibitory axis, leading to hyperactivation of glucose oxidation, eventually facilitating ovarian cancer cell motility and invasiveness.
Asunto(s)
Dinoprostona , Neoplasias Ováricas , Humanos , Femenino , Fosfofructoquinasas , Fosfofructoquinasa-1/genética , Hígado/metabolismo , Glucosa/metabolismo , Neoplasias Ováricas/patología , Proliferación Celular , Línea Celular Tumoral , Invasividad NeoplásicaRESUMEN
During microbial infection, macrophages link recognition of microbial stimuli to the induction of Type I inflammatory responses. Such inflammatory responses coordinate host defense and pathogen elimination but induce significant tissue damage if sustained, so macrophages are initially activated to induce inflammatory responses but then shift to a tolerant state to suppress inflammatory responses. Macrophage tolerance is regulated by induction of negative regulators of TLR signaling, but its metabolic basis was not known. Here, we review recent studies that indicate that macrophage metabolism changes dynamically over the course of microbial exposure to influence a shift in the inflammatory response. In particular, an initial increase in oxidative metabolism boosts the induction of inflammatory responses, but is followed by a shutdown of oxidative metabolism that contributes to suppression of inflammatory responses. We propose a unifying model for how dynamic changes to oxidative metabolism influences regulation of macrophage inflammatory responses during microbial exposure.
Asunto(s)
Inflamación/inmunología , Macrófagos/metabolismo , Estrés Oxidativo/inmunología , Animales , Humanos , Tolerancia Inmunológica , Inmunomodulación , Macrófagos/inmunología , Modelos Inmunológicos , Oxidación-Reducción , Receptores Toll-Like/metabolismoRESUMEN
Macrophages are cells of the innate immune system that regulate the maintenance of tissue homeostasis, host defense during pathogen infection, and tissue repair in response to tissue injury. Recent studies indicate that macrophage functions are influenced by cellular metabolism, including lipid metabolism. Here, we review how macrophage lipid metabolism can be dynamically altered in different physiological and pathophysiological contexts and the key regulators involved. We also describe how alterations in lipid metabolism are integrated with the signaling pathways that specify macrophage functions, allowing for coordinated control of macrophage biology. Finally, we discuss how dysregulated lipid metabolism contributes to perturbed macrophage functions in settings such as atherosclerosis and pathogen infections.