RESUMEN
IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.
Asunto(s)
Inmunidad Mucosa , Inmunoglobulina A , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Receptores de Leucotrieno B4 , Transducción de Señal , Animales , Metabolismo de los Lípidos/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina A/metabolismo , Transducción de Señal/inmunología , Ratones , Receptores de Leucotrieno B4/metabolismo , Receptores de Leucotrieno B4/inmunología , Ácido Araquidónico/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Femenino , Microbioma Gastrointestinal/inmunología , Ratones NoqueadosRESUMEN
Triple-negative breast cancer (TNBC) has become a thorny problem in the treatment of breast cancer because of its high invasiveness, metastasis and recurrence. Although immunotherapy has made important progress in TNBC, immune escape caused by many factors, especially metabolic reprogramming, is still the bottleneck of TNBC immunotherapy. Regrettably, the mechanisms responsible for immune escape remain poorly understood. Exploring the mechanism of TNBC immune escape at the metabolic level provides a target and direction for follow-up targeting or immunotherapy. In this review, we focus on the mechanism that TNBC affects immune cells and interstitial cells through hypoxia, glucose metabolism, lipid metabolism and amino acid metabolism, and changes tumor metabolism and tumor microenvironment. This will help to find new targets and strategies for TNBC immunotherapy.
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Neoplasias de la Mama Triple Negativas , Escape del Tumor , Microambiente Tumoral , Humanos , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/metabolismo , Microambiente Tumoral/inmunología , Femenino , Animales , Inmunoterapia/métodos , Metabolismo de los Lípidos/inmunología , Reprogramación Celular/inmunología , Reprogramación MetabólicaRESUMEN
Among the T helper cell subsets, Th17 cells contribute to the development of various inflammatory and autoimmune diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Retinoid-related orphan receptor gamma t (RORγt), a nuclear hormone receptor, serves as a master transcription factor for Th17 cell differentiation. Recent findings have shown that modulating the metabolic pathway is critical for Th17 cell differentiation, particularly through the engagement of de novo lipid biosynthesis. Suppression of lipid biosynthesis, either through the pharmacological inhibition or gene deletion of related enzymes in CD4+ T cells, results in significant impairment of Th17 cell differentiation. Mechanistic studies indicate that metabolic fluxes through both the fatty acid and cholesterol biosynthetic pathways have a pivotal role in the regulation of RORγt activity through the generation of endogenous RORγt lipid ligands. This review discusses recent discoveries highlighting the importance of lipid metabolism in Th17 cell differentiation and function, as well as exploring specific molecular pathways involved in RORγt activation through cellular lipid metabolism. We further elaborate on a pioneering therapeutic approach to improve inflammatory and autoimmune disorders via the inhibition of RORγt.
Asunto(s)
Diferenciación Celular , Metabolismo de los Lípidos , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Células Th17 , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Humanos , Diferenciación Celular/inmunología , Metabolismo de los Lípidos/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismoRESUMEN
BACKGROUND: Lipid metabolism affects type 2 immunity; however, the association between plasma lipids and eosinophilic inflammation in humans is uncertain. This study analysed the relationship between plasma lipids and peripheral eosinophils and whether patterns differ with different body mass indexes (BMI). METHODS: A cross-sectional survey including 62,441 healthy participants recruited from a regular health screening programme was conducted. Participants were divided into normal weight, overweight and obese subgroups according to BMI. RESULTS: Multiple linear regression analysis revealed that elevated logarithmic-transformed eosinophil counts (log(EOS)) significantly correlated with high total cholesterol(TC), triglyceride(TG), low-density lipoprotein-cholesterol (LDL-C), and low high-density lipoprotein-cholesterol (HDL-C)levels in the overall population, as well as in men and women, while certain associations between peripheral blood eosinophil percentage and serum lipids varied by gender. These correlations existed across almost all BMI subgroups, and standardised ß values decreased sequentially with increasing BMI. HDL-C had the most significant effect on eosinophils in obese women. Two-factor analysis of variance showed log(EOS) increased with higher BMI and hyperlipidemia whether in male or female and a synergistic effect exists of lipid levels (TG and LDL-C) and BMI in men. CONCLUSIONS: Blood eosinophil counts were correlated with blood lipid levels and modified by body mass index status. The effects of lipid levels and body mass index on blood eosinophil counts were synergistic. Therefore, lipid metabolism may be involved in systemic eosinophil inflammation.
Asunto(s)
Índice de Masa Corporal , Pueblos del Este de Asia , Eosinófilos , Inflamación , Lípidos , Femenino , Humanos , Masculino , LDL-Colesterol , Estudios Transversales , Eosinófilos/inmunología , Inflamación/sangre , Inflamación/inmunología , Lípidos/sangre , Metabolismo de los Lípidos/inmunologíaRESUMEN
Macrophage polarization is influenced by lipids, which also exert significant control over macrophage functions. Lipids and their metabolites are players in intricate signaling pathways that modulate macrophages' responses to pathogens, phagocytosis, ferroptosis, and inflammation. This review focuses on lipid metabolism and macrophage functions and addresses potential molecular targets for the treatment of macrophage-related diseases. While lipogenesis is crucial for lipid accumulation and phagocytosis in M1 macrophages, M2 macrophages likely rely on fatty acid ß-oxidation to utilize fatty acids as their primary energy source. Cholesterol metabolism, regulated by factors such as SREBPs, PPARs, and LXRs, is associated with the cholesterol efflux capacity and the formation of foam cells (M2-like macrophages). Foam cells, which are targets for atherosclerosis, are associated with an increase in inflammatory cytokines. Lipolysis and fatty acid uptake markers, such as CD36, also contribute to the production of cytokines. Enhancing the immune system through the inhibition of lipid-metabolism-related factors can potentially serve as a targeted approach against tumor cells. Cyclooxygenase inhibitors, which block the conversion of arachidonic acid into various inflammatory mediators, influence macrophage polarization and have generated attention in cancer research.
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Polaridad Celular , Inflamación , Metabolismo de los Lípidos , Macrófagos , Neoplasias , Metabolismo de los Lípidos/inmunología , Polaridad Celular/inmunología , Inflamación/inmunología , Neoplasias/inmunología , Macrófagos/inmunología , Colesterol/metabolismo , Ácidos Grasos/metabolismo , Ferroptosis , HumanosRESUMEN
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation. We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells. We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness's mechanism of action.
Asunto(s)
Síndrome de Fatiga Crónica , Ácidos Grasos , Linfocitos , Humanos , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Síndrome de Fatiga Crónica/inmunología , Células Asesinas Naturales , Ácidos Grasos/inmunología , Oxidación-Reducción , Metabolismo de los Lípidos/inmunología , Linfocitos/inmunología , Subgrupos Linfocitarios/inmunologíaRESUMEN
Despite all the advances of modern medicine, atherosclerosis continues to be one of the most important medical and social problems. Atherosclerosis is the cause of several cardiovascular diseases, which are associated with high rates of disability and mortality. The development of atherosclerosis is associated with the accumulation of lipids in the arterial intima and the disruption of mechanisms that maintain the balance between the development and resolution of inflammation. Fatty acids are involved in many mechanisms of inflammation development and maintenance. Endothelial cells demonstrate multiple cross-linkages between lipid metabolism and innate immunity. In addition, these processes are linked to hemodynamics and the function of other cells in the vascular wall, highlighting the central role of the endothelium in vascular biology.
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Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Ácidos Grasos/metabolismo , Animales , Enfermedades Cardiovasculares/metabolismo , Eicosanoides/metabolismo , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Ácidos Grasos/inmunología , Hemodinámica , Humanos , Inmunidad Innata , Inflamación/inmunología , Inflamación/metabolismo , Metabolismo de los Lípidos/inmunología , Metabolismo de los Lípidos/fisiología , Lípidos/fisiología , Túnica Íntima/metabolismoRESUMEN
BACKGROUND: KRAS is the predominant oncogene mutated in pancreatic ductal adenocarcinoma (PDAC), the fourth cause of cancer-related deaths worldwide. Mutant KRAS-driven tumors are metabolically programmed to support their growth and survival, which can be used to identify metabolic vulnerabilities. In the present study, we aimed to understand the role of extracellularly derived fatty acids in KRAS-driven pancreatic cancer. METHODS: To assess the dependence of PDAC cells on extracellular fatty acids we employed delipidated serum or RNAi-mediated suppression of ACSL3 (to inhibit the activation and cellular retention of extracellular fatty acids) followed by cell proliferation assays, qPCR, apoptosis assays, immunoblots and fluorescence microscopy experiments. To assess autophagy in vivo, we employed the KrasG12D/+;p53flox/flox;Pdx1-CreERT2 (KPC) mice crossed with Acsl3 knockout mice, and to assess the efficacy of the combination therapy of ACSL3 and autophagy inhibition we used xenografted human cancer cell-derived tumors in immunocompromised mice. RESULTS: Here we show that depletion of extracellularly derived lipids either by serum lipid restriction or suppression of ACSL3, triggers autophagy, a process that protects PDAC cells from the reduction of bioenergetic intermediates. Combined extracellular lipid deprivation and autophagy inhibition exhibits anti-proliferative and pro-apoptotic effects against PDAC cell lines in vitro and promotes suppression of xenografted human pancreatic cancer cell-derived tumors in mice. Therefore, we propose lipid deprivation and autophagy blockade as a potential co-targeting strategy for PDAC treatment. CONCLUSIONS: Our work unravels a central role of extracellular lipid supply in ensuring fatty acid provision in cancer cells, unmasking a previously unappreciated metabolic vulnerability of PDAC cells.
Asunto(s)
Autofagia/inmunología , Metabolismo de los Lípidos/inmunología , Neoplasias Pancreáticas/terapia , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Humanos , Ratones , Neoplasias Pancreáticas/patología , Neoplasias PancreáticasRESUMEN
Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Cardiovasculares/inmunología , Dislipidemias/inmunología , Metabolismo de los Lípidos/inmunología , Enfermedades Reumáticas/inmunología , Enfermedades Autoinmunes/terapia , Enfermedades Cardiovasculares/terapia , Dislipidemias/terapia , Humanos , Inflamación/inmunología , Inflamación/terapia , Enfermedades Reumáticas/terapiaRESUMEN
Secreted phospholipase A2-IIA (sPLA2-IIA) hydrolyzes phospholipids to liberate lysophospholipids and fatty acids. Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes bacterial membranes. Here, we show that sPLA2-IIA affects the immune system by acting on the intestinal microbial flora. Using mice overexpressing transgene-driven human sPLA2-IIA, we found that the intestinal microbiota was critical for both induction of an immune phenotype and promotion of inflammatory arthritis. The expression of sPLA2-IIA led to alterations of the intestinal microbiota composition, but housing in a more stringent pathogen-free facility revealed that its expression could affect the immune system in the absence of changes to the composition of this flora. In contrast, untargeted lipidomic analysis focusing on bacteria-derived lipid mediators revealed that sPLA2-IIA could profoundly alter the fecal lipidome. The data suggest that a singular protein, sPLA2-IIA, produces systemic effects on the immune system through its activity on the microbiota and its lipidome.
Asunto(s)
Artritis , Fenómenos Fisiológicos Bacterianos/inmunología , Microbioma Gastrointestinal/fisiología , Fosfolipasas A2 Grupo II/metabolismo , Metabolismo de los Lípidos/inmunología , Animales , Animales Modificados Genéticamente , Artritis/inmunología , Artritis/microbiología , Humanos , Fenómenos del Sistema Inmunológico , Lipidómica/métodos , Ratones , Modelos Animales , Patología Molecular/métodos , TransgenesRESUMEN
BACKGROUND & AIMS: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism. METHODS: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model. RESULTS: PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-à-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes. CONCLUSIONS: Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism. LAY SUMMARY: There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males.
Asunto(s)
Exposición a Riesgos Ambientales/efectos adversos , Metabolismo de los Lípidos/fisiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Adulto , Aminoácidos/análisis , Aminoácidos/sangre , Animales , Estudios de Cohortes , Modelos Animales de Enfermedad , Exposición a Riesgos Ambientales/estadística & datos numéricos , Ácidos Grasos no Esterificados/análisis , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Metabolismo de los Lípidos/inmunología , Masculino , Ratones , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Immunosuppressive myeloid cells play a major role in cancer by negatively regulating immune responses, promoting tumor progression, and limiting the efficacy of cancer immunotherapy. Immunosuppression is mediated by various mechanisms dependent upon the type of myeloid cell involved. In recent years, a more universal mechanism of immunosuppressive activity of myeloid cells has emerged: Generation of oxidized lipids. Oxidized lipids accumulate in all types of myeloid cells and are often transferred between cells. In this review, we discuss mechanisms involved in the generation and biological role of myeloid cell-derived oxidized lipids in cancer.
Asunto(s)
Tolerancia Inmunológica , Metabolismo de los Lípidos/inmunología , Células Mieloides/inmunología , Células Mieloides/metabolismo , Neoplasias/inmunología , Neoplasias/metabolismo , Microambiente Tumoral/inmunología , Animales , Humanos , Neoplasias/patología , Oxidación-ReducciónRESUMEN
Chronic inflammation plays a critical role in the pathogenesis of atherosclerosis. Currently, the mechanism(s) by which inflammation contributes to this disease are not entirely understood. Inflammation is known to induce oxidative stress, which can lead to lipid peroxidation. Lipid peroxidation can result in the production of reactive by-products that can oxidatively modify macromolecules including DNA, proteins, and lipoproteins. A major reactive by-product of lipid peroxidation is malondialdehyde (MDA). MDA can subsequently break down to form acetaldehyde (AA). These two aldehydes can covalently interact with the epsilon (ε)-amino group of lysines within proteins and lipoproteins leading to the formation of extremely stable, highly immunogenic malondialdehyde/acetaldehyde adducts (MAA-adducts). The aim of this study was to investigate the inflammatory response to MAA-modified human serum albumin (HSA-MAA) and low-density lipoprotein (LDL-MAA). We found that animals injected with LDL-MAA generate antibodies specific to MAA-adducts. The level of anti-MAA antibodies were further increased in an animal model of atherosclerosis fed a Western diet. An animal model that combined both high fat diet and immunization of MAA-modified protein resulted in a dramatic increase in antibodies to MAA-adducts and vascular fat accumulation compared with controls. In vitro exposure of endothelial cells and macrophages to MAA-modified proteins resulted in increased fat accumulation as well as increased expression of adhesion molecules and pro-inflammatory cytokines. The expression of cytokines varied between the different cell lines and was unique to the individual modified proteins. The results of these studies demonstrate that different MAA-modified proteins elicit unique responses in different cell types. Additionally, the presence of MAA-modified proteins appears to modulate cellular metabolism leading to increased accumulation of triglycerides and further progression of the inflammatory response.
Asunto(s)
Inflamación/metabolismo , Lipoproteínas LDL/inmunología , Lipoproteínas LDL/metabolismo , Procesamiento Proteico-Postraduccional , Albúmina Sérica Humana/inmunología , Albúmina Sérica Humana/metabolismo , Acetaldehído/metabolismo , Animales , Aterosclerosis/etiología , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/metabolismo , Moléculas de Adhesión Celular/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animales de Enfermedad , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Femenino , Humanos , Inflamación/etiología , Inflamación/inmunología , Metabolismo de los Lípidos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratas , Ratas Sprague-DawleyRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is closely related to glycolipid metabolism and liver inflammation. And there is no effective drug approved for its clinical therapy. In this study, we focused on mangiferin (Man) and explored its effects and mechanisms on NAFLD treatment based on the regulation of glycolipid metabolism and anti-inflammatory in vivo and in vitro. The results exhibited that Man can significantly attenuate liver injury, insulin resistance, and glucose tolerance in high-fat diet- (HFD-) induced NAFLD mice and significantly reduce fat accumulation and inflammation in hepatic tissue of NAFLD mice. The transcriptome level RNA-seq analysis showed that the significantly different expression genes between the Man treatment group and the HFD-induced NAFLD model group were mainly related to regulation of energy, metabolism, and inflammation in liver tissue. Furthermore, western blots, real-time PCR, and immunohistochemistry experiments confirmed that Man significantly activated the AMPK signal pathway and inhibited NLRP3 inflammasome activation and pyroptosis in NAFLD mice. In in vitro cell experiments, we further confirmed that Man can promote glucose consumption and reduce intracellular triglyceride (TG) accumulation induced by free fatty acids in HepG2 cells and further that it can be blocked by AMPK-specific inhibitors. Western blot results showed that Man upregulated p-AMPKα levels and exhibited a significant AMPK activation effect, which was blocked by compound C. At the same time, Man downregulated the expression of NLRP3 inflammasome-related proteins and inhibited the activation of NLRP3 inflammasome, alleviating cell pyroptosis and inflammation effects. These results indicate that Man anti-NAFLD activity is mediated through its regulation of glucolipid metabolism by AMPK activation and its anti-inflammatory effects by NLRP3 inflammasome inhibition. Our study indicates that Man is a promising prodrug for the therapy of NAFLD patients.
Asunto(s)
Proteínas Quinasas Activadas por AMP/antagonistas & inhibidores , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Xantonas/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Células Hep G2 , Humanos , Inflamasomas/antagonistas & inhibidores , Inflamasomas/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/inmunología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/patología , Masculino , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/patología , Piroptosis/efectos de los fármacos , Piroptosis/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Xantonas/uso terapéuticoRESUMEN
Myeloid-derived suppressor cells (MDSCs) impede antitumor immunity; however, the precise mechanisms that regulate their suppressive function remain unresolved. Identifying these mechanisms could lead to therapeutic interventions to boost cancer immunotherapy efficacy. Here, we reveal that ß2 adrenergic receptor (ß2-AR) expression on MDSCs increases with tumor growth and that the ß2-AR stress pathway drives the immune suppressive activity of MDSCs by altering their metabolism. We show that ß2-AR signaling decreases glycolysis and increases oxidative phosphorylation and fatty acid oxidation (FAO). It also increases expression of the fatty acid transporter CPT1A, which is necessary for the FAO-mediated immunosuppressive function of MDSCs. Moreover, we show that ß2-AR signaling increases autophagy and activates the arachidonic acid cycle, both required for increasing the release of the immunosuppressive mediator, PGE2. Our data reveal that ß2-AR signaling triggered by stress is an important physiological regulator of key metabolic pathways in MDSCs, driving their immunosuppressive function.
Asunto(s)
Células Supresoras de Origen Mieloide/metabolismo , Proteínas de Neoplasias/inmunología , Neoplasias/inmunología , Receptores Adrenérgicos beta 2/inmunología , Transducción de Señal/inmunología , Microambiente Tumoral/inmunología , Animales , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/inmunología , Ratones , Ratones Noqueados , Proteínas de Neoplasias/genética , Neoplasias/genética , Fosforilación Oxidativa , Receptores Adrenérgicos beta 2/genética , Microambiente Tumoral/genéticaRESUMEN
Rheumatoid arthritis (RA) is a systemic autoimmune disease. Synovial hyperplasia and persistent inflammation serve as its typical pathological manifestations, which ultimately lead to joint destruction and function loss. Both clinical observations and metabolomics studies have revealed the prevalence of metabolic disorders in RA. In inflammatory immune microenvironments, energy metabolism is profoundly changed. Increasingly evidences suggest that this abnormality is involved in the occurrence and development of RA-related inflammation. Unsurprisingly, many energy metabolism sensors have been confirmed with immunoregulatory properties. As a representative, silent information regulator type 1 (Sirt1) controls many aspects of immune cells, such as cell lifespan, polarization, and secretion by functioning as a transcriptional regulator. Because of the profound clinical implication, researches on Sirt1 in the regulation of energy metabolism and immune functions under RA conditions have gradually gained momentum. This signaling balances glycolysis, lipid metabolism and insulin secretion orchestrating with other metabolism sensors, and consequently affects immune milieu through a so-called metabolism-immune feedback mechanism. This article reviews the involvement of Sirt1 in RA by discussing its impacts on energy metabolism and immune functions, and specially highlights the potential of Sirt1-targeting anti-rheumatic regimens. It also provides a theoretical basis for clarifying the mystery about the high incidence of metabolic complications in RA patients and identifying new anti-rheumatic reagents.
Asunto(s)
Artritis Reumatoide/inmunología , Metabolismo Energético/inmunología , Sirtuina 1/metabolismo , Animales , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Glucólisis/efectos de los fármacos , Glucólisis/inmunología , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Sirtuina 1/antagonistas & inhibidores , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/inmunología , Membrana Sinovial/patologíaRESUMEN
Interleukin (IL)-6 has been studied since its discovery for its role in health and diseases. It is one of the most important pro-inflammatory cytokines. IL-6 was reported as an exacerbating factor in coronavirus disease. In recent years, it has become clear that the function of muscle-derived IL-6 is different from what has been reported so far. Exercise is accompanied by skeletal muscle contraction, during which, several bioactive substances, collectively named myokines, are secreted from the muscles. Many reports have shown that IL-6 is the most abundant myokine. Interestingly, it was indicated that IL-6 plays opposing roles as a myokine and as a pro-inflammatory cytokine. In this review, we discuss why IL-6 has different functions, the signaling mode of hyper-IL-6 via soluble IL-6 receptor (sIL-6R), and the involvement of soluble glycoprotein 130 in the suppressive effect of hyper-IL-6. Furthermore, the involvement of a disintegrin and metalloprotease family molecules in the secretion of sIL-6R is described. One of the functions of muscle-derived IL-6 is lipid metabolism in the liver. However, the differences between the functions of IL-6 as a pro-inflammatory cytokine and the functions of muscle-derived IL-6 are unclear. Although the involvement of myokines in lipid metabolism in adipocytes was previously discussed, little is known about the direct relationship between nonalcoholic fatty liver disease and muscle-derived IL-6. This review is the first to discuss the relationship between the function of IL-6 in diseases and the function of muscle-derived IL-6, focusing on IL-6 signaling and lipid metabolism in the liver.
Asunto(s)
Interleucina-6/metabolismo , Metabolismo de los Lípidos/inmunología , Hígado/metabolismo , Músculos/metabolismo , Receptores de Interleucina-6/metabolismo , Adipocitos/inmunología , Adipocitos/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Hígado/inmunología , Ratones , Músculos/inmunología , Transducción de Señal/inmunologíaRESUMEN
Autoimmune polyendocrine syndrome type I (APS-1) is a monogenic model disorder of organ-specific autoimmunity caused by mutations in the Autoimmune regulator (AIRE) gene. AIRE facilitates the expression of organ-specific transcripts in the thymus, which is essential for efficient removal of dangerous self-reacting T cells and for inducing regulatory T cells (Tregs). Although reduced numbers and function of Tregs have been reported in APS-I patients, the impact of AIRE deficiency on gene expression in these cells is unknown. Here, we report for the first time on global transcriptional patterns of isolated Tregs from APS-1 patients compared to healthy subjects. Overall, we found few differences between the groups, although deviant expression was observed for the genes TMEM39B, SKIDA1, TLN2, GPR15, FASN, BCAR1, HLA-DQA1, HLA-DQB1, HLA-DRA, GPSM3 and AKR1C3. Of significant interest, the consistent downregulation of GPR15 may indicate failure of Treg gut homing which could be of relevance for the gastrointestinal manifestations commonly seen in APS-1. Upregulated FASN expression in APS-1 Tregs points to increased metabolic activity suggesting a putative link to faulty Treg function. Functional studies are needed to determine the significance of these findings for the immunopathogenesis of APS-1 and for Treg immunobiology in general.
Asunto(s)
Acido Graso Sintasa Tipo I/metabolismo , Poliendocrinopatías Autoinmunes/inmunología , Poliendocrinopatías Autoinmunes/metabolismo , Linfocitos T Reguladores/inmunología , Adulto , Estudios de Casos y Controles , Acido Graso Sintasa Tipo I/genética , Femenino , Humanos , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Metabolismo de los Lípidos/inmunología , Masculino , Persona de Mediana Edad , Poliendocrinopatías Autoinmunes/genética , Linfocitos T Reguladores/metabolismoRESUMEN
An adverse intrauterine environment impairs the development of pancreatic islets in the fetus and leads to insufficient ß cell mass and ß cell dysfunction. We previously reported that Pex14, a peroxin protein involved in the biogenesis and degradation of peroxisomes, is markedly reduced in the pancreas of an intrauterine growth restriction fetus and last into adulthood. Peroxisomes function in a wide range of metabolic processes including fatty acid oxidization, ROS detoxification, and anti-inflammatory responses. To elucidate the impact of downregulation of the Pex14 gene on ß cell, Pex14 was knocked down by siRNA in INS-1 cells. Pex14 knockdown disturbed peroxisomal biogenesis and dysregulated fatty acid metabolism and lipid storage capability, thereby increased ROS level and blunted insulin secretion. Moreover, Pex14 knockdown upregulated inflammation factors and regulators of endoplasmic reticulum stress. The lipotoxicity of fatty acid (including palmitic acid and linoleic acid) in ß cells was exacerbated by knockdown of Pex14, as indicated by H2O2 accumulation and increased programmed cell death. The present results demonstrate the vital role of Pex14 in maintaining normal peroxisome function and ß cell viability and highlight the importance of a functional peroxisomal metabolism for the detoxification of excess FAs in ß cells.
Asunto(s)
Retardo del Crecimiento Fetal/fisiopatología , Metabolismo de los Lípidos/inmunología , Proteínas de la Membrana/metabolismo , Peroxisomas/patología , Proteínas Represoras/metabolismo , Animales , Apoptosis , Linfocitos B , Humanos , Ratas , TransfecciónRESUMEN
Non-alcoholic steatohepatitis (NASH), an extreme progressive subtype of metabolic associated fatty liver disease, is well characterized by hepatic steatosis, injury and inflammation. It causes irreversible hepatic damage and there are no approved interventions for it. ß-PAE, a representatively pharmacological active substance isolated from Pogostemon cablin, has been indicated to alleviate hepatic steatosis and injury through modulating lipid metabolism in rats with simple steatosis. However, its protection against NASH remains unclear. Here, this study explored the potential effect of ß-PAE against high-fat diet-induced NASH in rats. The results displayed that ß-PAE significantly reduced the gains of body weight and epididymal adipose tissue, liver index and attenuated liver histological damages in NASH rats. It also markedly alleviated hepatic inflammation by inhibiting NLRP3 inflammasome activation. In NASH, the active NLRP3 inflammasome is caused by hepatic lipid abnormal accumulation-induced oxidative stress. Excessive oxidative stress results in hepatic histanoxia, which exacerbates lipid metabolism disorders by elevating CD36 to suppress AMPK signalling pathways. Moreover, the lipid accumulation led by lipid metabolism dysfunction intensifies oxidative stress. A vicious circle is formed among oxidative stress, histanoxia and lipid accumulation, eventually, but ß-PAE effectively interrupted it. Interestingly, soluble CD36 (sCD36) was tightly associated not only with hepatic steatosis and injury but also with inflammation. Collectively, ß-PAE exerted a positive effect against NASH by interrupting the vicious circle among oxidative stress, histanoxia and lipid accumulation, and sCD36 may be a promising non-invasive tool for NASH diagnosis.