RESUMO
The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies (TNFSF/TNFRSF) include 19 ligands and 29 receptors that play important roles in the modulation of cellular functions. The communication pathways mediated by TNFSF/TNFRSF are essential for numerous developmental, homeostatic, and stimulus-responsive processes in vivo. TNFSF/TNFRSF members regulate cellular differentiation, survival, and programmed death, but their most critical functions pertain to the immune system. Both innate and adaptive immune cells are controlled by TNFSF/TNFRSF members in a manner that is crucial for the coordination of various mechanisms driving either co-stimulation or co-inhibition of the immune response. Dysregulation of these same signaling pathways has been implicated in inflammatory and autoimmune diseases, highlighting the importance of their tight regulation. Investigation of the control of TNFSF/TNFRSF activities has led to the development of therapeutics with the potential to reduce chronic inflammation or promote anti-tumor immunity. The study of TNFSF/TNFRSF proteins has exploded over the last 30 yr, but there remains a need to better understand the fundamental mechanisms underlying the molecular pathways they mediate to design more effective anti-inflammatory and anti-cancer therapies.
Assuntos
Sistema Imunitário/metabolismo , Inflamação/imunologia , Ligantes , Receptores do Fator de Necrose Tumoral/metabolismo , Fatores de Necrose Tumoral/metabolismo , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Humanos , Inflamação/metabolismoRESUMO
Activated T cells produce reactive oxygen species (ROS), which trigger the antioxidative glutathione (GSH) response necessary to buffer rising ROS and prevent cellular damage. We report that GSH is essential for T cell effector functions through its regulation of metabolic activity. Conditional gene targeting of the catalytic subunit of glutamate cysteine ligase (Gclc) blocked GSH production specifically in murine T cells. Gclc-deficient T cells initially underwent normal activation but could not meet their increased energy and biosynthetic requirements. GSH deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of NFAT and Myc transcription factors, abrogating the energy utilization and Myc-dependent metabolic reprogramming that allows activated T cells to switch to glycolysis and glutaminolysis. In vivo, T-cell-specific ablation of murine Gclc prevented autoimmune disease but blocked antiviral defense. The antioxidative GSH pathway thus plays an unexpected role in metabolic integration and reprogramming during inflammatory T cell responses.
Assuntos
Glutamato-Cisteína Ligase/deficiência , Glutationa/metabolismo , Inflamação/metabolismo , Linfócitos T/metabolismo , Animais , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Metabolismo Energético/genética , Glutamato-Cisteína Ligase/genética , Glutamina/metabolismo , Glicólise , Immunoblotting , Inflamação/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição NFATC/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
T cells are a central component of defenses against pathogens and tumors. Their effector functions are sustained by specific metabolic changes that occur upon activation, and these have been the focus of renewed interest. Energy production inevitably generates unwanted products, namely reactive oxygen species (ROS), which have long been known to trigger cell death. However, there is now evidence that ROS also act as intracellular signaling molecules both in steady-state and upon antigen recognition. The levels and localization of ROS contribute to the redox modeling of effector proteins and transcription factors, influencing the outcome of the T cell response. We discuss here how ROS can directly fine-tune metabolism and effector functions of T cells.
Assuntos
Metabolismo Energético , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Glicólise , Humanos , Mitocôndrias/metabolismo , Modelos BiológicosRESUMO
Drosophila, like other invertebrates and plants, relies mainly on RNA interference for its defense against viruses. In flies, viral infection also triggers the expression of many genes. One of the genes induced, Vago, encodes a 18-kilodalton cysteine-rich polypeptide. Here we provide genetic evidence that the Vago gene product controlled viral load in the fat body after infection with drosophila C virus. Induction of Vago was dependent on the helicase Dicer-2. Dicer-2 belongs to the same DExD/H-box helicase family as do the RIG-I-like receptors, which sense viral infection and mediate interferon induction in mammals. We propose that this family represents an evolutionary conserved set of sensors that detect viral nucleic acids and direct antiviral responses.
Assuntos
Proteínas de Drosophila/imunologia , Drosophila/imunologia , Drosophila/virologia , RNA Helicases/imunologia , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Eletroforese em Gel de Poliacrilamida , Corpo Adiposo/imunologia , Corpo Adiposo/virologia , Regulação da Expressão Gênica/imunologia , Humanos , Filogenia , RNA Helicases/genética , RNA Helicases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonuclease III , Homologia de Sequência de Aminoácidos , Transcrição Gênica , Viroses/imunologiaRESUMO
The fruit fly Drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity and has led to some important discoveries about the sensing and signaling of microbial infections. The response of Drosophila to virus infections remains poorly characterized and appears to involve two facets. On the one hand, RNA interference involves the recognition and processing of dsRNA into small interfering RNAs by the host RNase Dicer-2 (Dcr-2), whereas, on the other hand, an inducible response controlled by the evolutionarily conserved JAK-STAT pathway contributes to the antiviral host defense. To clarify the contribution of the small interfering RNA and JAK-STAT pathways to the control of viral infections, we have compared the resistance of flies wild-type and mutant for Dcr-2 or the JAK kinase Hopscotch to infections by seven RNA or DNA viruses belonging to different families. Our results reveal a unique susceptibility of hop mutant flies to infection by Drosophila C virus and cricket paralysis virus, two members of the Dicistroviridae family, which contrasts with the susceptibility of Dcr-2 mutant flies to many viruses, including the DNA virus invertebrate iridescent virus 6. Genome-wide microarray analysis confirmed that different sets of genes were induced following infection by Drosophila C virus or by two unrelated RNA viruses, Flock House virus and Sindbis virus. Overall, our data reveal that RNA interference is an efficient antiviral mechanism, operating against a large range of viruses, including a DNA virus. By contrast, the antiviral contribution of the JAK-STAT pathway appears to be virus specific.
Assuntos
Drosophila melanogaster/genética , Drosophila melanogaster/imunologia , Interferência de RNA/imunologia , Alphavirus/imunologia , Infecções por Alphavirus/genética , Infecções por Alphavirus/imunologia , Infecções por Alphavirus/prevenção & controle , Animais , Animais Geneticamente Modificados , Infecções por Vírus de DNA/genética , Infecções por Vírus de DNA/imunologia , Infecções por Vírus de DNA/prevenção & controle , Proteínas de Drosophila/genética , Proteínas de Drosophila/imunologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/virologia , Regulação da Expressão Gênica , Janus Quinases/metabolismo , Masculino , Nodaviridae/imunologia , RNA Helicases/genética , RNA Helicases/imunologia , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/imunologia , Infecções por Vírus de RNA/prevenção & controle , Ribonuclease III/genética , Ribonuclease III/imunologia , Fatores de Transcrição/metabolismoRESUMO
Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process. The inflammatory response must be actively terminated, however, because failure to do so can result in 'bystander' damage to tissues and diseases such as arthritis or type-2 diabetes. Yet the mechanisms controlling excessive inflammatory responses are still poorly understood. Here we show that mouse effector and memory CD4(+) T cells abolish macrophage inflammasome-mediated caspase-1 activation and subsequent interleukin 1beta release in a cognate manner. Inflammasome inhibition is observed for all tested NLRP1 (commonly called NALP1) and NLRP3 (NALP3 or cryopyrin) activators, whereas NLRC4 (IPAF) inflammasome function and release of other inflammatory mediators such as CXCL2, interleukin 6 and tumour necrosis factor are not affected. Suppression of the NLRP3 inflammasome requires cell-to-cell contact and can be mimicked by macrophage stimulation with selected ligands of the tumour necrosis factor family, such as CD40L (also known as CD40LG). In a NLRP3-dependent peritonitis model, effector CD4(+) T cells are responsible for decreasing neutrophil recruitment in an antigen-dependent manner. Our findings reveal an unexpected mechanism of inflammasome inhibition, whereby effector and memory T cells suppress potentially damaging inflammation, yet leave the primary inflammatory response, crucial for the onset of immunity, intact.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Linfócitos T CD4-Positivos/imunologia , Proteínas de Transporte/antagonistas & inibidores , Imunidade Inata/imunologia , Inflamação/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antígenos/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Células da Medula Óssea/citologia , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Células Cultivadas , Memória Imunológica , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/imunologia , Ligantes , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Neutrófilos/imunologia , Cavidade Peritoneal/citologia , Fatores de Necrose Tumoral/imunologia , Fatores de Necrose Tumoral/metabolismoRESUMO
Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1beta (IL-1beta) is a key pro-inflammatory factor in innate antifungal immunity. The mechanism by which the mammalian immune system regulates IL-1beta production after fungal recognition is unclear. Two signals are generally required for IL-1beta production: an NF-kappaB-dependent signal that induces the synthesis of pro-IL-1beta (p35), and a second signal that triggers proteolytic pro-IL-1beta processing to produce bioactive IL-1beta (p17) via Caspase-1-containing multiprotein complexes called inflammasomes. Here we demonstrate that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL-1beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1beta synthesis selectively uses the Card9 pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmalogical inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (also known as NALP3) was identified as the critical NOD-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (Pycard) for Caspase-1 (Casp1) activation and pro-IL-1beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, we show that Nlrp3-deficient mice are hypersusceptible to Candida albicans infection. Thus, our results demonstrate the molecular basis for IL-1beta production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.
Assuntos
Candida albicans/imunologia , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transdução de Sinais , Animais , Candida albicans/fisiologia , Caspase 1/metabolismo , Ativação Enzimática , Humanos , Inflamação/imunologia , Interleucina-1beta/biossíntese , Interleucina-1beta/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Macrófagos/metabolismo , Camundongos , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nigericina/farmacologia , Potássio/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Espécies Reativas de Oxigênio/metabolismo , Quinase SykRESUMO
The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.
Assuntos
Glutationa , Interleucina 22 , Interleucinas , Mitocôndrias , Células Th17 , Animais , Interleucinas/metabolismo , Mitocôndrias/metabolismo , Glutationa/metabolismo , Células Th17/metabolismo , Células Th17/imunologia , Camundongos , Transdução de Sinais , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos C57BL , Citrobacter rodentium , Intestinos/patologia , Intestinos/imunologia , Inflamação/metabolismo , Inflamação/patologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/metabolismo , Infecções por Enterobacteriaceae/patologia , Camundongos Knockout , Serina-Treonina Quinases TOR/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologiaRESUMO
Lymphocytic choriomeningitis virus (LCMV) is a frequently used animal model to study immune responses against acute and chronic viral infections. LCMV is a non-cytopathic virus, but destruction of infected cells by cytotoxic T lymphocytes (CTLs) can lead to severe damage of tissues. Virus-specific T cell responses have to be balanced. A low virus load leads to a strong T cell response and subsequently to viral control. In contrast, a high viral titer is associated with T cell exhaustion and chronic viral infections. During an intermediate LCMV viral load CD8+ T cells can cause immunopathology, which can have detrimental outcomes. The LCMV infection model offers the opportunity to study virus-specific CD4+ and CD8+ T cell responses during chronic and acute infections by quantifying LCMV-specific T cells by tetramer staining and measuring cytokine production and viral titers in different organs.
Assuntos
Coriomeningite Linfocítica , Vírus da Coriomeningite Linfocítica , Animais , Camundongos , Linfócitos T CD8-Positivos/patologia , Coriomeningite Linfocítica/patologia , Linfócitos T Citotóxicos , Camundongos Endogâmicos C57BLRESUMO
Pyruvate dehydrogenase (PDH) is the central enzyme connecting glycolysis and the tricarboxylic acid (TCA) cycle. The importance of PDH function in T helper 17 (Th17) cells still remains to be studied. Here, we show that PDH is essential for the generation of a glucose-derived citrate pool needed for Th17 cell proliferation, survival, and effector function. In vivo, mice harboring a T cell-specific deletion of PDH are less susceptible to developing experimental autoimmune encephalomyelitis. Mechanistically, the absence of PDH in Th17 cells increases glutaminolysis, glycolysis, and lipid uptake in a mammalian target of rapamycin (mTOR)-dependent manner. However, cellular citrate remains critically low in mutant Th17 cells, which interferes with oxidative phosphorylation (OXPHOS), lipid synthesis, and histone acetylation, crucial for transcription of Th17 signature genes. Increasing cellular citrate in PDH-deficient Th17 cells restores their metabolism and function, identifying a metabolic feedback loop within the central carbon metabolism that may offer possibilities for therapeutically targeting Th17 cell-driven autoimmunity.
Assuntos
Ácido Cítrico , Células Th17 , Camundongos , Animais , Citratos , Oxirredutases , Lipídeos , Piruvatos , MamíferosRESUMO
Although the intestinal tract is a major site of reactive oxygen species (ROS) generation, the mechanisms by which antioxidant defense in gut T cells contribute to intestinal homeostasis are currently unknown. Here we show, using T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that the ensuing loss of glutathione (GSH) impairs the production of gut-protective IL-22 by Th17 cells within the lamina propria. Although Gclc ablation does not affect T cell cytokine secretion in the gut of mice at steady-state, infection with C. rodentium increases ROS, inhibits mitochondrial gene expression and mitochondrial function in Gclc-deficient Th17 cells. These mitochondrial deficits affect the PI3K/AKT/mTOR pathway, leading to reduced phosphorylation of the translation repressor 4E-BP1. As a consequence, the initiation of translation is restricted, resulting in decreased protein synthesis of IL-22. Loss of IL-22 results in poor bacterial clearance, enhanced intestinal damage, and high mortality. ROS-scavenging, reconstitution of IL-22 expression or IL-22 supplementation in vivo prevent the appearance of these pathologies. Our results demonstrate the existence of a previously unappreciated role for Th17 cell-intrinsic GSH coupling to promote mitochondrial function, IL-22 translation and signaling. These data reveal an axis that is essential for maintaining the integrity of the intestinal barrier and protecting it from damage caused by gastrointestinal infection.
RESUMO
Macrophages undergo extensive metabolic reprogramming during classical pro-inflammatory polarization (M1-like). The accumulation of itaconate has been recognized as both a consequence and mediator of the inflammatory response. In this study we first examined the specific functions of itaconate inside fractionated mitochondria. We show that M1 macrophages produce itaconate de novo via aconitase decarboxylase 1 (ACOD1) inside mitochondria. The carbon for this reaction is not only supplied by oxidative TCA cycling, but also through the reductive carboxylation of α-ketoglutarate by isocitrate dehydrogenase (IDH). While macrophages are capable of sustaining a certain degree of itaconate production during hypoxia by augmenting the activity of IDH-dependent reductive carboxylation, we demonstrate that sufficient itaconate synthesis requires a balance of reductive and oxidative TCA cycle metabolism in mouse macrophages. In comparison, human macrophages increase itaconate accumulation under hypoxic conditions by augmenting reductive carboxylation activity. We further demonstrated that itaconate attenuates reductive carboxylation at IDH2, restricting its own production and the accumulation of the immunomodulatory metabolites citrate and 2-hydroxyglutarate. In line with this, reductive carboxylation is enhanced in ACOD1-depleted macrophages. Mechanistically, the inhibition of IDH2 by itaconate is linked to the alteration of the mitochondrial NADP+/NADPH ratio and competitive succinate dehydrogenase inhibition. Taken together, our findings extend the current model of TCA cycle reprogramming during pro-inflammatory macrophage activation and identified novel regulatory properties of itaconate.
Assuntos
Carboxiliases , Ciclo do Ácido Cítrico , Isocitrato Desidrogenase , Succinatos , Aconitato Hidratase/metabolismo , Animais , Carbono/metabolismo , Carboxiliases/metabolismo , Citratos , Retroalimentação , Humanos , Ácidos Cetoglutáricos/metabolismo , Camundongos , NADP/metabolismo , Succinato Desidrogenase/metabolismo , Succinatos/metabolismoRESUMO
Since its discovery in inflammatory macrophages, itaconate has attracted much attention due to its antimicrobial and immunomodulatory activity1-3. However, instead of investigating itaconate itself, most studies used derivatized forms of itaconate and thus the role of non-derivatized itaconate needs to be scrutinized. Mesaconate, a metabolite structurally very close to itaconate, has never been implicated in mammalian cells. Here we show that mesaconate is synthesized in inflammatory macrophages from itaconate. We find that both, non-derivatized itaconate and mesaconate dampen the glycolytic activity to a similar extent, whereas only itaconate is able to repress tricarboxylic acid cycle activity and cellular respiration. In contrast to itaconate, mesaconate does not inhibit succinate dehydrogenase. Despite their distinct impact on metabolism, both metabolites exert similar immunomodulatory effects in pro-inflammatory macrophages, specifically a reduction of interleukin (IL)-6 and IL-12 secretion and an increase of CXCL10 production in a manner that is independent of NRF2 and ATF3. We show that a treatment with neither mesaconate nor itaconate impairs IL-1ß secretion and inflammasome activation. In summary, our results identify mesaconate as an immunomodulatory metabolite in macrophages, which interferes to a lesser extent with cellular metabolism than itaconate.
Assuntos
Macrófagos , Succinatos , Animais , Inflamassomos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Succinatos/metabolismo , Succinatos/farmacologiaRESUMO
The NOD-like receptors (NLR) are a family of intracellular sensors of microbial motifs and 'danger signals' that have emerged as being crucial components of the innate immune responses and inflammation. Several NLRs (NALPs and IPAF) form a caspase-1-activating multiprotein complex, termed inflammasome, that processes proinflammatory cytokines including IL-1beta. Amongst the various inflammasomes, the NALP3 inflammasome is particularly qualified to sense a plethora of diverse molecules, ranging from bacterial muramyldipeptide to monosodium urate crystals. The important role of the NALP3 inflammasome is emphasized by the identification of mutations in the NALP3 gene that are associated with a susceptibility to inflammatory disorders. These and other issues related to the inflammasome are discussed in this review.
Assuntos
Proteínas de Transporte/imunologia , Caspases/metabolismo , Citocinas/metabolismo , Imunidade Inata , Receptores de Reconhecimento de Padrão/imunologia , Animais , Antígenos de Bactérias/imunologia , Proteínas de Transporte/metabolismo , Citocinas/imunologia , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLRRESUMO
Regulatory T cells (Tregs) maintain immune homeostasis and prevent autoimmunity. Serine stimulates glutathione (GSH) synthesis and feeds into the one-carbon metabolic network (1CMet) essential for effector T cell (Teff) responses. However, serine's functions, linkage to GSH, and role in stress responses in Tregs are unknown. Here, we show, using mice with Treg-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), that GSH loss in Tregs alters serine import and synthesis and that the integrity of this feedback loop is critical for Treg suppressive capacity. Although Gclc ablation does not impair Treg differentiation, mutant mice exhibit severe autoimmunity and enhanced anti-tumor responses. Gclc-deficient Tregs show increased serine metabolism, mTOR activation, and proliferation but downregulated FoxP3. Limitation of cellular serine in vitro and in vivo restores FoxP3 expression and suppressive capacity of Gclc-deficient Tregs. Our work reveals an unexpected role for GSH in restricting serine availability to preserve Treg functionality.
Assuntos
Glutationa/metabolismo , Serina/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , CamundongosRESUMO
The last ten years of research in the field of innate immunity have been incredibly fertile: the transmembrane Toll-like receptors (TLRs) were discovered as guardians protecting the host against microbial attacks and the emerging pathways characterized in detail. More recently, cytoplasmic sensors were identified, which are capable of detecting not only microbial, but also self molecules. Importantly, while such receptors trigger crucial host responses to microbial insult, over-activity of some of them has been linked to autoinflammatory disorders, hence demonstrating the importance of tightly regulating their actions over time and space. Here, we provide an overview of recent findings covering this area of innate and inflammatory responses that originate from the cytoplasm.
Assuntos
Receptores de Reconhecimento de Padrão/fisiologia , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , DNA Viral/farmacologia , Humanos , Interferon Tipo I/biossíntese , Proteínas Adaptadoras de Sinalização NOD/genética , Proteínas Adaptadoras de Sinalização NOD/fisiologia , RNA Viral/farmacologia , Receptores de Reconhecimento de Padrão/genéticaRESUMO
Tumor necrosis factor (TNF) is tremendously important for mammalian immunity and cellular homeostasis. The role of TNF as a master regulator in balancing cell survival, apoptosis and necroptosis has been extensively studied in various cell types and tissues. Although these findings have revealed much about the direct impact of TNF on the regulation of NF-κB and JNK, there is now rising interest in understanding the emerging function of TNF as a regulator of the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review we summarize work aimed at defining the role of TNF in the control of ROS/RNS signaling that influences innate immune cells under both physiological and inflammatory conditions.
Assuntos
Homeostase/imunologia , Espécies Reativas de Nitrogênio/imunologia , Espécies Reativas de Oxigênio/imunologia , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Apoptose , Sobrevivência Celular , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Linfócitos/imunologia , Linfócitos/patologia , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Necrose/genética , Necrose/imunologia , Necrose/patologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
Neuroinflammation is the local reaction of the brain to infection, trauma, toxic molecules or protein aggregates. The brain resident macrophages, microglia, are able to trigger an appropriate response involving secretion of cytokines and chemokines, resulting in the activation of astrocytes and recruitment of peripheral immune cells. IL-1ß plays an important role in this response; yet its production and mode of action in the brain are not fully understood and its precise implication in neurodegenerative diseases needs further characterization. Our results indicate that the capacity to form a functional NLRP3 inflammasome and secretion of IL-1ß is limited to the microglial compartment in the mouse brain. We were not able to observe IL-1ß secretion from astrocytes, nor do they express all NLRP3 inflammasome components. Microglia were able to produce IL-1ß in response to different classical inflammasome activators, such as ATP, Nigericin or Alum. Similarly, microglia secreted IL-18 and IL-1α, two other inflammasome-linked pro-inflammatory factors. Cell stimulation with α-synuclein, a neurodegenerative disease-related peptide, did not result in the release of active IL-1ß by microglia, despite a weak pro-inflammatory effect. Amyloid-ß peptides were able to activate the NLRP3 inflammasome in microglia and IL-1ß secretion occurred in a P2X7 receptor-independent manner. Thus microglia-dependent inflammasome activation can play an important role in the brain and especially in neuroinflammatory conditions.