RESUMO
Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
Assuntos
COVID-19 , Estudo de Associação Genômica Ampla , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , COVID-19/genética , Caracteres Sexuais , Loci Gênicos , Predisposição Genética para DoençaRESUMO
It is becoming clear that several human pathologies are caused by altered metabolic adaptations. During liver development, there are physiological changes, from the predominant utilization of glucose (fetal life) to the use of lipids (postnatal life). Fasting is another physiological stress that elicits well-known metabolic adjustments. We have reported the metabolic properties of cardiotrophin-1 (CT-1), a member of the interleukin-6 family of cytokines. Here, we aimed at analyzing the role of CT-1 in response to these metabolic changes. We used different in vivo models. Furthermore, a differential study was carried out with wild-type and CT-1 null mice in fed (ad libitum) and food-restricted conditions. We demonstrated that Ct-1 is a metabolic gene induced in the liver via PPARα in response to lipids in mice (neonates- and food-restricted adults). We found that Ct-1 mRNA expression in white adipose tissue directly involved PPARα and PPARγ. Finally, the physiological role of CT-1 in fasting is confirmed by the impaired food restriction-induced adipose tissue lipid mobilization in CT-1 null mice. Our findings support a previously unrecognized physiological role of CT-1 in metabolic adaptations, through the regulation of lipid metabolism and contributes to fasting-induced free fatty acid mobilization.
Assuntos
Adaptação Fisiológica/fisiologia , Jejum/metabolismo , Metabolismo dos Lipídeos/fisiologia , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Células 3T3 , Tecido Adiposo Branco/metabolismo , Animais , Linhagem Celular , Citocinas/metabolismo , Ácidos Graxos/metabolismo , Glucose/metabolismo , Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR alfa/metabolismo , PPAR gama/metabolismo , RNA Mensageiro/metabolismoRESUMO
Macrophages play a central role in tissue remodeling, repair, and resolution of inflammation. Macrophage polarization to M1 or M2 activation status may determine the progression or resolution of the inflammatory response. We have previously reported that cardiotrophin-1 (CT-1) displays both cytoprotective and metabolic activities. The role of CT-1 in inflammation remains poorly understood. Here, we employed recombinant CT-1 (rCT-1) and used CT-1-null mice and myeloid-specific CT-1 transgenic mice to investigate whether CT-1 might play a role in the modulation of the inflammatory response. We observed that CT-1 deficiency was associated with enhanced release of inflammatory mediators and with stronger activation of NF-κB in response to LPS, whereas the inflammatory response was attenuated in CT-1 transgenic mice or by administering rCT-1 to wild-type animals prior to LPS challenge. We found that CT-1 promoted IL-6 expression only by nonhematopoietic cells, whereas LPS up-regulated IL-6 expression in both hematopoietic and nonhematopoietic cells. Notably, rCT-1 inhibited LPS-mediated soluble IL-6R induction. Using IL-6-/- mice, we showed that rCT-1 inhibited LPS-induced TNF-α and IFN-γ response in an IL-6-independent manner. Importantly, we demonstrated that CT-1 primes macrophages for IL-4-dependent M2 polarization by inducing IL-4 receptor expression. Mechanistic analyses showed that the signal transducer and activator of transcription 3-suppressor of cytokine signaling 3 axis mediates this effect. Our findings support the notion that CT-1 is a critical regulator of inflammation and suggest that rCT-1 could be a molecule with potential therapeutic application in inflammatory conditions.-Carneros, D., Santamaría, E. M., Larequi, E., Vélez-Ortiz, J. M., Reboredo, M., Mancheño, U., Perugorria, M. J., Navas, P., Romero-Gómez, M., Prieto, J., Hervás-Stubbs, S., Bustos, M. Cardiotrophin-1 is an anti-inflammatory cytokine and promotes IL-4-induced M2 macrophage polarization.
Assuntos
Polaridade Celular , Citocinas/fisiologia , Inflamação/prevenção & controle , Interleucina-4/fisiologia , Macrófagos/citologia , Animais , Interleucina-6/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Cardiotrophin (CT)-1 is a regulator of glucose and lipid homeostasis. In the present study, we analyzed whether CT-1 also acts to peripherally regulate metabolic rhythms and adipose tissue core clock genes in mice. Moreover, the circadian pattern of plasma CT-1 levels was evaluated in normal-weight and overweight subjects. The circadian rhythmicity of oxygen consumption rate (Vo2) was disrupted in aged obese CT-1-deficient (CT-1-/-) mice (12 mo). Although circadian rhythms of Vo2 were conserved in young lean CT-1-/- mice (2 mo), CT-1 deficiency caused a phase shift of the acrophase. Most of the clock genes studied (Clock, Bmal1, and Per2) displayed a circadian rhythm in adipose tissue of both wild-type (WT) and CT-1-/- mice. However, the pattern was altered in CT-1-/- mice toward a lower percentage of the rhythm or lower amplitude, especially for Bmal1 and Clock. Moreover, CT-1 mRNA levels in adipose tissue showed significant circadian fluctuations in young WT mice. In humans, CT-1 plasma profile exhibited a 24-h circadian rhythm in normal-weight but not in overweight subjects. The 24-h pattern of CT-1 was characterized by a pronounced increase during the night (from 02:00 to 08:00). These observations suggest a potential role for CT-1 in the regulation of metabolic circadian rhythms.-López-Yoldi, M., Stanhope, K. L., Garaulet, M., Chen, X. G., Marcos-Gómez, B., Carrasco-Benso, M. P., Santa Maria, E. M., Escoté, X., Lee, V., Nunez, M. V., Medici, V., Martínez-Ansó, E., Sáinz, N., Huerta, A. E., Laiglesia, L. M., Prieto, J., Martínez, J. A., Bustos, M., Havel, P. J., Moreno-Aliaga, M. J. Role of cardiotrophin-1 in the regulation of metabolic circadian rhythms and adipose core clock genes in mice and characterization of 24-h circulating CT-1 profiles in normal-weight and overweight/obese subjects.
Assuntos
Tecido Adiposo/metabolismo , Proteínas CLOCK/genética , Ritmo Circadiano , Citocinas/metabolismo , Obesidade/metabolismo , Tecido Adiposo/fisiologia , Adolescente , Adulto , Animais , Proteínas CLOCK/metabolismo , Citocinas/sangue , Citocinas/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Consumo de OxigênioRESUMO
Cardiotrophin-1 (CT-1) belongs to the IL-6 family of cytokines. Previous studies of our group revealed that CT-1 is a key regulator of glucose and lipid metabolism. The aim of the present study was to analyze the in vitro and in vivo effects of CT-1 on the production of several adipokines involved in body weight regulation, nutrient metabolism, and inflammation. For this purpose, 3T3-L1 adipocytes were incubated with recombinant protein CT-1 (rCT-1) (1-40 ng/ml) for 1 and 18 h. Moreover, the acute effects of rCT-1 administration (0.2 mg/kg, i.v.) for 30 min and 3 h on adipokines levels were also evaluated in high-fat fed obese mice. In 3T3-L1 adipocytes, rCT-1 treatment downregulated the expression and secretion of leptin, resistin, and visfatin. However, rCT-1 significantly stimulated apelin mRNA and secretion. rCT-1 (18 h) also promoted the activation by phosphorylation of AKT, ERK 1/2, and STAT3. Interestingly, pre-treatment with the PI3K inhibitor LY294002 reversed the stimulatory effects of rCT-1 on apelin expression, suggesting that this pathway could be mediating the effects of rCT-1 on apelin production. In contrast, acute administration of rCT-1 (30 min and 3 h) to diet-induced obese mice downregulated leptin and resistin, without significantly modifying apelin or visfatin mRNA in adipose tissue. Furthermore, CT-1 null mice exhibited altered expression of adipokines in adipose tissue. The present study demonstrates that rCT-1 modulates the production of adipokines in vitro and in vivo, suggesting that the regulation of the secretory function of adipocytes could be involved in the metabolic actions of this cytokine. J. Cell. Physiol. 232: 2469-2477, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Adipócitos/metabolismo , Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Citocinas/metabolismo , Obesidade/metabolismo , Células 3T3-L1 , Adipocinas/genética , Animais , Apelina , Citocinas/deficiência , Citocinas/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nicotinamida Fosforribosiltransferase/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/fisiopatologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resistina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de SinaisRESUMO
Besides its role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5HT) regulates inflammation and tissue repair via a set of receptors (5HT(1-7)) whose pattern of expression varies among cell lineages. Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair, we evaluated whether 5HT modulates human macrophage polarization. 5HT inhibited the LPS-induced release of proinflammatory cytokines without affecting IL-10 production, upregulated the expression of M2 polarization-associated genes (SERPINB2, THBS1, STAB1, COL23A1), and reduced the expression of M1-associated genes (INHBA, CCR2, MMP12, SERPINE1, CD1B, ALDH1A2). Whereas only 5HT(7) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines, both 5HT(2B) and 5HT(7) receptors mediated the pro-M2 skewing effect of 5HT. In fact, blockade of both receptors during in vitro monocyte-to-macrophage differentiation preferentially modulated the acquisition of M2 polarization markers. 5HT(2B) was found to be preferentially expressed by anti-inflammatory M2(M-CSF) macrophages and was detected in vivo in liver Kupffer cells and in tumor-associated macrophages. Therefore, 5HT modulates macrophage polarization and contributes to the maintenance of an anti-inflammatory state via 5HT(2B) and 5HT(7), whose identification as functionally relevant markers for anti-inflammatory/homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies.
Assuntos
Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Receptor 5-HT2B de Serotonina/imunologia , Receptores de Serotonina/imunologia , Serotonina/farmacologia , Animais , Linhagem da Célula , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Genes Reporter , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-10/biossíntese , Interleucina-10/imunologia , Células de Kupffer/citologia , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/imunologia , Lipopolissacarídeos , Luciferases , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor 5-HT2B de Serotonina/genética , Receptores de Serotonina/genética , Serotonina/imunologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Cardiotrophin-1 (CT-1) is a cytokine with antiobesity properties and with a role in lipid metabolism regulation and adipose tissue function. The aim of this study was to analyze the molecular mechanisms involved in the lipolytic actions of CT-1 in adipocytes. Recombinant CT-1 (rCT-1) effects on the main proteins and signaling pathways involved in the regulation of lipolysis were evaluated in 3T3-L1 adipocytes and in mice. rCT-1 treatment stimulated basal glycerol release in a concentration- and time-dependent manner in 3T3-L1 adipocytes. rCT-1 (20 ng/ml for 24 h) raised cAMP levels, and in parallel increased protein kinase (PK)A-mediated phosphorylation of perilipin and hormone sensitive lipase (HSL) at Ser660. siRNA knock-down of HSL or PKA, as well as pretreatment with the PKA inhibitor H89, blunted the CT-1-induced lipolysis, suggesting that the lipolytic action of CT-1 in adipocytes is mainly mediated by activation of HSL through the PKA pathway. In ob/ob mice, acute rCT-1 treatment also promoted PKA-mediated phosphorylation of perilipin and HSL at Ser660 and Ser563, and increased adipose triglyceride lipase (desnutrin) content in adipose tissue. These results showed that the ability of CT-1 to regulate the activity of the main lipases underlies the lipolytic action of this cytokine in vitro and in vivo, and could contribute to CT-1 antiobesity effects.
Assuntos
Adipócitos Brancos/metabolismo , Proteínas de Transporte/metabolismo , Citocinas/metabolismo , Lipase/metabolismo , Lipólise , Fosfoproteínas/metabolismo , Esterol Esterase/metabolismo , Regulação para Cima , Células 3T3-L1 , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/enzimologia , Animais , Proteínas de Transporte/biossíntese , Proteínas de Ciclo Celular/agonistas , Proteínas de Ciclo Celular/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de AMP Cíclico/química , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citocinas/genética , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Inativação Gênica , Lipase/antagonistas & inibidores , Lipase/química , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Mutantes , Perilipina-1 , Fosfoproteínas/biossíntese , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional , Proteínas Recombinantes/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esterol Esterase/antagonistas & inibidores , Esterol Esterase/química , Esterol Esterase/genética , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND & AIMS: Cardiotrophin-1 (CT-1) is a hepatoprotective cytokine that modulates fat and glucose metabolism in muscle and adipose tissue. Here we analyzed the changes in hepatic fat stores induced by recombinant CT-1 (rCT-1) and its therapeutic potential in non-alcoholic fatty liver disease (NAFLD). METHODS: rCT-1 was administered to two murine NAFLD models: ob/ob and high fat diet-fed mice. Livers were analyzed for lipid composition and expression of genes involved in fat metabolism. We studied the effects of rCT-1 on lipogenesis and fatty acid (FA) oxidation in liver cells and the ability of dominant negative inhibitor of AMP-activated protein kinase (AMPK) to block these effects. RESULTS: CT-1 was found to be upregulated in human and murine steatotic livers. In two NAFLD mouse models, treatment with rCT-1 for 10days induced a marked decrease in liver triglyceride content with augmented proportion of poly-unsaturated FA and reduction of monounsaturated species. These changes were accompanied by attenuation of inflammation and improved insulin signaling. Chronic administration of rCT-1 caused downregulation of lipogenic genes and genes involved in FA import to hepatocytes together with amelioration of ER stress, elevation of NAD(+)/NADH ratio, phosphorylation of LKB1 and AMPK, increased expression and activity of sirtuin1 (SIRT1) and upregulation of genes mediating FA oxidation. rCT-1 potently inhibited de novo lipogenesis and stimulated FA oxidation in liver cells both in vitro and in vivo. In vitro studies showed that these effects are mediated by activated AMPK. CONCLUSIONS: rCT-1 resolves hepatic steatosis in obese mice by mechanisms involving AMPK activation. rCT-1 deserves consideration as a potential therapy for NAFLD.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Citocinas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Citocinas/genética , Citocinas/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ativação Enzimática , Ácidos Graxos/metabolismo , Hepatócitos/metabolismo , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos , Lipogênese , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Sirtuína 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/metabolismo , Regulação para CimaRESUMO
BACKGROUND: SARS-CoV-2 infection is considered as a relapsing inflammatory process with a dysregulation of IL-6 signalling. Classic IL-6 signalling is thought to represent a defence mechanism against pathogens. In contrast, IL-6 trans-signalling has pro-inflammatory effects. In severe COVID-19, therapeutic strategies have focused on global inhibition of IL-6, with controversial results. We hypothesized that specific blockade of IL-6 trans-signalling could inhibit inflammatory response preserving the host defence activity inherent to IL-6 classic signalling. METHODS: To test the role of the specific IL-6 trans-signalling inhibition by sgp130Fc in short- and long-term consequences of COVID-19, we used the established K18-hACE2 transgenic mouse model. Histological as well as immunohistochemical analysis, and pro-inflammatory marker profiling were performed. To investigate IL-6 trans-signalling in human cells we used primary lung microvascular endothelial cells and fibroblasts in the presence/absence of sgp130Fc. FINDINGS: We report that targeting IL-6 trans-signalling by sgp130Fc attenuated SARS-CoV-2-related clinical symptoms and mortality. In surviving mice, the treatment caused a significant decrease in lung damage. In vitro, IL-6 trans-signalling induced strong and persisting JAK1/STAT3 activation in endothelial cells and lung fibroblasts with proinflammatory effects, which were attenuated by sgp130Fc. Our data also suggest that in those cells with scant amounts of IL-6R, the induction of gp130 and IL-6 by IL-6:sIL-6R complex sustains IL-6 trans-signalling. INTERPRETATION: IL-6 trans-signalling fosters progression of COVID-19, and suggests that specific blockade of this signalling mode could offer a promising alternative to mitigate both short- and long-term consequences without affecting the beneficial effects of IL-6 classic signalling. These results have implications for the development of new therapies of lung injury and endotheliopathy in COVID-19. FUNDING: The project was supported by ISCIII, Spain (COV-20/00792 to MB, PI23/01351 to MARH) and the European Commission-Next generation EU (European Union) (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global, SGL2103029 to MB). PID2019-110587RB-I00 (MB) supported by MICIN/AEI/10.13039/501100011033/and PID2022-143034OB-I00 (MB) by MICIN/AEI/10.13039/501100011033/FEDER. MAR-H acknowledges support from ISCIII, Spain and the European Commission-Next generation EU (European Union), through CSIC's Global Health PTI.
Assuntos
COVID-19 , Receptor gp130 de Citocina , Interleucina-6 , Camundongos Transgênicos , SARS-CoV-2 , Transdução de Sinais , Animais , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Infecções por Coronavirus/patologia , COVID-19/metabolismo , Tratamento Farmacológico da COVID-19 , Receptor gp130 de Citocina/metabolismo , Receptor gp130 de Citocina/antagonistas & inibidores , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Interleucina-6/metabolismo , Pulmão/patologia , Pulmão/virologia , Pulmão/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Pneumonia Viral/patologia , Pneumonia Viral/metabolismo , Receptores de Interleucina-6/metabolismo , Receptores de Interleucina-6/antagonistas & inibidores , Proteínas Recombinantes de Fusão/farmacologia , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacosRESUMO
The enormous societal impact of the ongoing COVID-19 pandemic has been particularly harsh for some social groups, such as the elderly. Recently, it has been suggested that senescent cells could play a central role in pathogenesis by exacerbating the pro-inflammatory immune response against SARS-CoV-2. Therefore, the selective clearance of senescent cells by senolytic drugs may be useful as a therapy to ameliorate the symptoms of COVID-19 in some cases. Using the established COVID-19 murine model K18-hACE2, we demonstrated that a combination of the senolytics dasatinib and quercetin (D/Q) significantly reduced SARS-CoV-2-related mortality, delayed its onset, and reduced the number of other clinical symptoms. The increase in senescent markers that we detected in the lungs in response to SARS-CoV-2 may be related to the post-COVID-19 sequelae described to date. These results place senescent cells as central targets for the treatment of COVID-19, and make D/Q a new and promising therapeutic tool.
Assuntos
COVID-19 , Quercetina , Camundongos , Humanos , Animais , Quercetina/farmacologia , Quercetina/uso terapêutico , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , SARS-CoV-2 , Senescência Celular , Senoterapia , PandemiasRESUMO
Monocyte-derived macrophages, the major source of pathogenic macrophages in COVID-19, are oppositely instructed by macrophage CSF (M-CSF) or granulocyte macrophage CSF (GM-CSF), which promote the generation of antiinflammatory/immunosuppressive MAFB+ (M-MØ) or proinflammatory macrophages (GM-MØ), respectively. The transcriptional profile of prevailing macrophage subsets in severe COVID-19 led us to hypothesize that MAFB shapes the transcriptome of pulmonary macrophages driving severe COVID-19 pathogenesis. We have now assessed the role of MAFB in the response of monocyte-derived macrophages to SARS-CoV-2 through genetic and pharmacological approaches, and we demonstrate that MAFB regulated the expression of the genes that define pulmonary pathogenic macrophages in severe COVID-19. Indeed, SARS-CoV-2 potentiated the expression of MAFB and MAFB-regulated genes in M-MØ and GM-MØ, where MAFB upregulated the expression of profibrotic and neutrophil-attracting factors. Thus, MAFB determines the transcriptome and functions of the monocyte-derived macrophage subsets that underlie pulmonary pathogenesis in severe COVID-19 and controls the expression of potentially useful biomarkers for COVID-19 severity.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , COVID-19/metabolismo , Macrófagos/metabolismo , Macrófagos Alveolares/metabolismo , Biomarcadores/metabolismo , Fator de Transcrição MafB/genética , Fator de Transcrição MafB/metabolismoRESUMO
Obesity is a complex disease caused by the interaction of a myriad of genetic, dietary, lifestyle and environmental factors, which favors a chronic positive energy balance, leading to increased body fat mass. There is emerging evidence of a strong association between obesity and an increased risk of cancer. However, the mechanisms linking both diseases are not fully understood. Here, we analyze the current knowledge about the potential contribution that expanding adipose tissue in obesity could make to the development of cancer via dysregulated secretion of pro-inflammatory cytokines, chemokines and adipokines such as TNF-α, IL-6, leptin, adiponectin, visfatin and PAI-1. Dietary factors play an important role in the risk of suffering obesity and cancer. The identification of bioactive dietary factors or substances that affect some of the components of energy balance to prevent/reduce weight gain as well as cancer is a promising avenue of research. This article reviews the beneficial effects of some bioactive food molecules (n-3 PUFA, CLA, resveratrol and lipoic acid) in energy metabolism and cancer, focusing on the molecular mechanisms involved, which may provide new therapeutic targets in obesity and cancer.
Assuntos
Tecido Adiposo/patologia , Neoplasias/complicações , Nutrigenômica , Obesidade/complicações , Tecido Adiposo/metabolismo , Animais , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Alimentos , Humanos , Redes e Vias Metabólicas/genética , Modelos Biológicos , Neoplasias/dietoterapia , Neoplasias/metabolismo , Neoplasias/patologia , Nutrigenômica/métodos , Obesidade/dietoterapia , Obesidade/metabolismo , Obesidade/patologiaRESUMO
Ischemia-reperfusion (I/R) liver injury occurs when blood flow is restored after prolonged ischemia. A short interruption of blood flow (ischemic preconditioning [IP]) induces tolerance to subsequent prolonged ischemia through ill-defined mechanisms. Cardiotrophin (CT)-1, a cytokine of the interleukin-6 family, exerts hepatoprotective effects and activates key survival pathways like JAK/STAT3. Here we show that administration of CT-1 to rats or mice protects against I/R liver injury and that CT-1-deficient mice are exceedingly sensitive to this type of damage. IP markedly reduced transaminase levels and abrogated caspase-3 and c-Jun-NH2-terminal kinase activation after I/R in normal mice but not in CT-1-null mice. Moreover, the protective effect afforded by IP was reduced by previous administration of neutralizing anti-CT-1 antibody. Prominent STAT3 phosphorylation in liver tissue was observed after IP plus I/R in normal mice but not in CT-1-null mice. Oxidative stress, a process involved in IP-induced hepatoprotection, was found to stimulate CT-1 release from isolated hepatocytes. Interestingly, brief ischemia followed by short reperfusion caused mild serum transaminase elevation and strong STAT3 activation in normal and IL-6-deficient mice, but failed to activate STAT3 and provoked marked hypertransaminasemia in CT-1-null animals. In conclusion, CT-1 is an essential endogenous defense of the liver against I/R and is a key mediator of the protective effect induced by IP.
Assuntos
Citocinas/fisiologia , Precondicionamento Isquêmico , Traumatismo por Reperfusão/metabolismo , Alanina Transaminase/sangue , Animais , Anticorpos/farmacologia , Aspartato Aminotransferases/sangue , Western Blotting , Caspase 3/metabolismo , Citocinas/genética , Citocinas/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/fisiologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/patologia , Fator de Transcrição STAT3/metabolismo , terc-Butil Hidroperóxido/farmacologiaRESUMO
Rabbit hemorrhagic disease virus (RHDV) causes lethal fulminant hepatitis closely resembling acute liver failure (ALF) in humans. In this study, we investigated whether cardiotrophin-1 (CT-1), a cytokine with hepatoprotective properties, could attenuate liver damage and prolong survival in virus-induced ALF. Twenty-four rabbits were infected with 2 × 10(4) hemagglutination units of RHDV. Twelve received five doses of CT-1 (100 µg/kg) starting at 12 h postinfection (hpi) (the first three doses every 6 h and then two additional doses at 48 and 72 hpi), while the rest received saline. The animals were analyzed for survival, serum biochemistry, and viral load. Another cohort (n = 22) was infected and treated similarly, but animals were sacrificed at 30 and 36 hpi to analyze liver histology, viral load, and the expression of factors implicated in liver damage and repair. All infected rabbits that received saline died by 60 hpi, while 67% of the CT-1-treated animals survived until the end of the study. Treated animals showed improved liver function and histology, while the viral loads were similar. In the livers of CT-1-treated rabbits we observed reduction of oxidative stress, diminished PARP1/2 and JNK activation, and decreased inflammatory reaction, as reflected by reduced expression of tumor necrosis factor alpha, interleukin-1ß, Toll-like receptor 4, VCAM-1, and MMP-9. In addition, CT-1-treated rabbits exhibited marked upregulation of TIMP-1 and increased expression of cytoprotective and proregenerative growth factors, including platelet-derived growth factor B, epidermal growth factor, platelet-derived growth factor receptor ß, and c-Met. In conclusion, in a lethal form of acute viral hepatitis, CT-1 increases animal survival by attenuating inflammation and activating cytoprotective mechanisms, thus representing a promising therapy for ALF of viral origin.
Assuntos
Infecções por Caliciviridae/veterinária , Citocinas/administração & dosagem , Vírus da Doença Hemorrágica de Coelhos/patogenicidade , Hepatite Viral Animal/tratamento farmacológico , Hepatite Viral Animal/mortalidade , Fatores Imunológicos/administração & dosagem , Animais , Análise Química do Sangue , Western Blotting , Infecções por Caliciviridae/tratamento farmacológico , Infecções por Caliciviridae/mortalidade , Perfilação da Expressão Gênica , Histocitoquímica , Humanos , Fígado/patologia , Fígado/virologia , Testes de Função Hepática , Coelhos , Análise de Sobrevida , Carga ViralRESUMO
During inflammatory responses, monocytes are recruited into inflamed tissues, where they become monocyte-derived macrophages and acquire pro-inflammatory and tissue-damaging effects in response to the surrounding environment. In fact, monocyte-derived macrophage subsets are major pathogenic cells in inflammatory pathologies. Strikingly, the transcriptome of pathogenic monocyte-derived macrophage subsets resembles the gene profile of macrophage colony-stimulating factor (M-CSF)-primed monocyte-derived human macrophages (M-MØ). As M-MØ display a characteristic cytokine profile after activation (IL10high TNFlow IL23low IL6low), we sought to determine the transcriptional signature of M-MØ upon exposure to pathogenic stimuli. Activation of M-MØ led to the acquisition of a distinctive transcriptional profile characterized by the induction of a group of genes (Gene set 1) highly expressed by pathogenic monocyte-derived macrophages in COVID-19 and whose presence in tumor-associated macrophages (TAM) correlates with the expression of macrophage-specific markers (CD163, SPI1) and IL10. Indeed, Gene set 1 expression was primarily dependent on ERK/p38 and STAT3 activation, and transcriptional analysis and neutralization experiments revealed that IL-10 is not only required for the expression of a subset of genes within Gene set 1 but also significantly contributes to the idiosyncratic gene signature of activated M-MØ. Our results indicate that activation of M-CSF-dependent monocyte-derived macrophages induces a distinctive gene expression profile, which is partially dependent on IL-10, and identifies a gene set potentially helpful for macrophage-centered therapeutic strategies.
Assuntos
COVID-19 , Fator Estimulador de Colônias de Macrófagos , Diferenciação Celular , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismoRESUMO
IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal via different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables [IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)] and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.
Assuntos
COVID-19 , Interleucina-6 , Receptores de Interleucina-6 , Transdução de Sinais , COVID-19/diagnóstico , COVID-19/imunologia , Receptor gp130 de Citocina/metabolismo , Humanos , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , Índice de Gravidade de DoençaRESUMO
IL-6 family cytokines are defined by the common use of the signal-transducing receptor chain glycoprotein 130 (gp130). Increasing evidence indicates that these cytokines are essential in the regulation of metabolic homeostasis as well as in the pathophysiology of multiple gastrointestinal and liver disorders, thus making them attractive therapeutic targets. Over the past few years, therapies modulating gp130 signalling have grown exponentially in several clinical settings including obesity, cancer and inflammatory bowel disease. A newly engineered gp130 cytokine, IC7Fc, has shown promising preclinical results for the treatment of type 2 diabetes, obesity and liver steatosis. Moreover, drugs that modulate gp130 signalling have shown promise in refractory inflammatory bowel disease in clinical trials. A deeper understanding of the main roles of the IL-6 family of cytokines during homeostatic and pathological conditions, their signalling pathways, sources of production and target cells will be crucial to the development of improved treatments. Here, we review the current state of the role of these cytokines in hepatology and gastroenterology and discuss the progress achieved in translating therapeutics targeting gp130 signalling into clinical practice.
Assuntos
Receptor gp130 de Citocina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Interleucina-6/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Animais , Citocinas/metabolismo , Citocinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Imunoglobulina G/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Transdução de SinaisRESUMO
UNLABELLED: Human LSECtin (liver and lymph node sinusoidal endothelial cell C-type lectin, CLEC4G) is a C-type lectin encoded within the L-SIGN/DC-SIGN/CD23 gene cluster. LSECtin acts as a pathogen attachment factor for Ebolavirus and the SARS coronavirus, and its expression can be induced by interleukin-4 on monocytes and macrophages. Although reported as a liver and lymph node sinusoidal endothelial cell-specific molecule, LSECtin could be detected in the MUTZ-3 dendritic-like cell line at the messenger RNA (mRNA) and protein level, and immunohistochemistry analysis on human liver revealed its presence in Kupffer cells coexpressing the myeloid marker CD68. The expression of LSECtin in myeloid cells was further corroborated through the analysis of the proximal regulatory region of the human LSECtin gene, whose activity was maximal in LSECtin+ myeloid cells, and which contains a highly conserved PU.1-binding site. PU.1 transactivated the LSECtin regulatory region in collaboration with hematopoietic-restricted transcription factors (Myb, RUNX3), and was found to bind constitutively to the LSECtin proximal promoter. Moreover, knockdown of PU.1 through the use of small interfering RNA led to a decrease in LSECtin mRNA levels in THP-1 and monocyte-derived dendritic cells, thus confirming the involvement of PU.1 in the myeloid expression of the lectin. CONCLUSION: LSECtin is expressed by liver myeloid cells, and its expression is dependent on the PU.1 transcription factor.
Assuntos
Células de Kupffer/metabolismo , Lectinas Tipo C/biossíntese , Proteínas Proto-Oncogênicas/fisiologia , Transativadores/fisiologia , Animais , Humanos , Fígado/citologia , Camundongos , Células Mieloides/metabolismo , Células NIH 3T3 , RNA Mensageiro/metabolismoRESUMO
Non-alcoholic fatty liver disease (NAFLD) is a major health problem, and its prevalence has increased in recent years. Diet and exercise interventions are the first-line treatment options, with weight loss via a hypocaloric diet being the most important therapeutic target in NAFLD. However, most NAFLD patients are not able to achieve such weight loss. Therefore, the requisite is the investigation of other effective therapeutic approaches. This review summarizes research on understanding complex pathophysiology underlying dietary approaches and exercise interventions with the potential to prevent and treat NAFLD.