RESUMEN
In the version of this article initially published, author Alexandre Prat's surname was misspelled. The error has been corrected in the HTML and PDF versions of the article.
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Tumor-associated macrophages (TAMs) play an important role in the immune response to cancer, but the mechanisms by which the tumor microenvironment controls TAMs and T cell immunity are not completely understood. Here we report that kynurenine produced by glioblastoma cells activates aryl hydrocarbon receptor (AHR) in TAMs to modulate their function and T cell immunity. AHR promotes CCR2 expression, driving TAM recruitment in response to CCL2. AHR also drives the expression of KLF4 and suppresses NF-κB activation in TAMs. Finally, AHR drives the expression of the ectonucleotidase CD39 in TAMs, which promotes CD8+ T cell dysfunction by producing adenosine in cooperation with CD73. In humans, the expression of AHR and CD39 was highest in grade 4 glioma, and high AHR expression was associated with poor prognosis. In summary, AHR and CD39 expressed in TAMs participate in the regulation of the immune response in glioblastoma and constitute potential targets for immunotherapy.
Asunto(s)
Antígenos CD/metabolismo , Apirasa/metabolismo , Neoplasias Encefálicas/inmunología , Glioblastoma/inmunología , Quinurenina/metabolismo , Macrófagos/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Linfocitos T/metabolismo , Animales , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Glioblastoma/metabolismo , Humanos , Factor 4 Similar a Kruppel , Receptores de Lipopolisacáridos/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/metabolismo , Factor de Transcripción STAT1 , Factor de Transcripción STAT3/metabolismo , Linfocitos T/inmunología , Microambiente TumoralRESUMEN
Interleukin 10 receptor (IL10R)-deficient mice develop spontaneous colitis and, similarly, patients with loss-of-function mutations in IL10R develop severe infant-onset inflammatory bowel disease. Loss of IL10R signaling in mouse and human macrophages is associated with increased production of interleukin 1ß. We demonstrated that innate immune production of IL1ß mediates colitis in IL10R-deficient mice. Transfer of Il1r1-/- CD4+ T cells into Rag1-/-/Il10rb-/- mice reduced the severity of their colitis (compared to mice that received CD4+ T cells that express IL1R), accompanied by decreased production of interferon gamma, tumor necrosis factor-α, and IL17A. In macrophages from mice without disruption of IL10R signaling or from healthy humans (controls), incubation with IL10 reduced canonical activation of the inflammasome and production of IL1ß through transcriptional and post-translational regulation of NLRP3. Lipopolysaccharide and adenosine triphosphate stimulation of macrophages from Il10rb-/- mice or IL10R-deficient patients resulted in increased production of IL1ß. Moreover, in human IL10R-deficient macrophages, lipopolysaccharide stimulation alone triggered IL1ß secretion via non-canonical, caspase 8-dependent activation of the inflammasome. We treated 2 IL10R-deficient patients with severe and treatment-refractory infant-onset inflammatory bowel disease with the IL1-receptor antagonist anakinra. Both patients had marked clinical, endoscopic, and histologic responses after 4-7 weeks. This treatment served as successful bridge to allogeneic hematopoietic stem cell transplantation in 1 patient. Our findings indicate that loss of IL10 signaling leads to intestinal inflammation, at least in part, through increased production of IL1 by innate immune cells, leading to activation of CD4+ T cells. Agents that block IL1 signaling might be used to treat patients with inflammatory bowel disease resulting from IL10R deficiency.
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Colitis/inmunología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Receptores de Interleucina-10/genética , Adenosina Trifosfato/farmacología , Adulto , Animales , Antirreumáticos/uso terapéutico , Linfocitos T CD4-Positivos , Caspasa 8/metabolismo , Células Cultivadas , Preescolar , Colitis/genética , Colitis/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de Homeodominio/genética , Humanos , Inmunidad Innata , Inflamasomas/efectos de los fármacos , Inflamasomas/metabolismo , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Interferón gamma/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-10/farmacología , Subunidad alfa del Receptor de Interleucina-10/genética , Interleucina-17/metabolismo , Interleucina-1beta/genética , Lipopolisacáridos/farmacología , Macrófagos , Ratones , Ratones Noqueados , Mutación , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Receptores de Interleucina-10/deficiencia , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Type 1 diabetes (T1D) is a T cell-dependent autoimmune disease that is characterized by the destruction of insulin-producing ß cells in the pancreas. The administration to patients of ex vivo-differentiated FoxP3(+) regulatory T (Treg) cells or tolerogenic dendritic cells (DCs) that promote Treg cell differentiation is considered a potential therapy for T1D; however, cell-based therapies cannot be easily translated into clinical practice. We engineered nanoparticles (NPs) to deliver both a tolerogenic molecule, the aryl hydrocarbon receptor (AhR) ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), and the ß cell antigen proinsulin (NPITE+Ins) to induce a tolerogenic phenotype in DCs and promote Treg cell generation in vivo. NPITE+Ins administration to 8-week-old nonobese diabetic mice suppressed autoimmune diabetes. NPITE+Ins induced a tolerogenic phenotype in DCs, which was characterized by a decreased ability to activate inflammatory effector T cells and was concomitant with the increased differentiation of FoxP3(+) Treg cells. The induction of a tolerogenic phenotype in DCs by NPs was mediated by the AhR-dependent induction of Socs2, which resulted in inhibition of nuclear factor κB activation and proinflammatory cytokine production (properties of tolerogenic DCs). Together, these data suggest that NPs constitute a potential tool to reestablish tolerance in T1D and potentially other autoimmune disorders.
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Diabetes Mellitus Tipo 1/inmunología , Células Secretoras de Insulina/inmunología , Proteínas Supresoras de la Señalización de Citocinas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/agonistas , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patología , Humanos , Indoles/química , Indoles/farmacología , Células Secretoras de Insulina/patología , Ratones Endogámicos NOD , Nanopartículas/química , Nanopartículas/uso terapéutico , Receptores de Hidrocarburo de Aril/agonistas , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/inmunología , Proteínas Supresoras de la Señalización de Citocinas/genética , Linfocitos T Reguladores/patología , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-ß are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation.
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Astrocitos/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Microbioma Gastrointestinal , Interferón Tipo I/inmunología , Esclerosis Múltiple/inmunología , Receptores de Hidrocarburo de Aril/inmunología , Linfocitos T/inmunología , Triptófano/metabolismo , Animales , Estudios de Casos y Controles , Proliferación Celular , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Quimiocina CCL2/metabolismo , Inmunoprecipitación de Cromatina , Cromatografía Líquida de Alta Presión , Encefalomielitis Autoinmune Experimental/metabolismo , Técnica del Anticuerpo Fluorescente , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Immunoblotting , Indicán/orina , Indoles/metabolismo , Inflamación , Interferón beta/farmacología , Limosilactobacillus reuteri , Ratones , Ratones Noqueados , Esclerosis Múltiple/metabolismo , Proteínas de Resistencia a Mixovirus/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Imagen Óptica , Reacción en Cadena de la Polimerasa , Receptor de Interferón alfa y beta/genética , Receptores de Hidrocarburo de Aril/metabolismo , Factor de Transcripción STAT1/metabolismo , Serotonina , Proteínas Supresoras de la Señalización de Citocinas , Triptofanasa/metabolismoRESUMEN
Seasonal changes in disease activity have been observed in multiple sclerosis, an autoimmune disorder that affects the CNS. These epidemiological observations suggest that environmental factors influence the disease course. Here, we report that melatonin levels, whose production is modulated by seasonal variations in night length, negatively correlate with multiple sclerosis activity in humans. Treatment with melatonin ameliorates disease in an experimental model of multiple sclerosis and directly interferes with the differentiation of human and mouse T cells. Melatonin induces the expression of the repressor transcription factor Nfil3, blocking the differentiation of pathogenic Th17 cells and boosts the generation of protective Tr1 cells via Erk1/2 and the transactivation of the IL-10 promoter by ROR-α. These results suggest that melatonin is another example of how environmental-driven cues can impact T cell differentiation and have implications for autoimmune disorders such as multiple sclerosis.
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Melatonina/metabolismo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Diferenciación Celular , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Luz , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Recurrencia , Estaciones del Año , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/citología , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory T cell (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular ATP (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen-presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response.
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Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunidad Celular , Inflamación/inmunología , Receptores de Hidrocarburo de Aril/metabolismo , Linfocitos T Reguladores/metabolismo , Adulto , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Apirasa/inmunología , Apirasa/metabolismo , Diferenciación Celular/inmunología , Femenino , Hematopoyesis/inmunología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/inmunología , Inflamación/metabolismo , Inflamación/patología , Activación de Linfocitos/inmunología , Ratones , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study, we identified a context-dependent effect of the nonsteroidal anti-inflammatory drug indomethacin (IND) on MDSCs, depending on whether they were derived from tumor microenvironments (TME) or from tumor-free microenvironments (TFME). Treatment of mice bearing the LP07 lung adenocarcinoma with IND inhibited the suppressive activity of splenic MDSCs, which restrained tumor growth through mechanisms involving CD8(+) T cells. The same effect was observed when MDSCs were treated with IND and conditioned media from LP07 tumor cells in vitro. However, in the absence of a tumor context, IND enhanced the intrinsic suppressive function of MDSCs and amplified their protumoral activity. In a model of autoimmune neuroinflammation, IND-treated MDSCs differentiated in TFME attenuated inflammation, whereas IND-treated MDSCs differentiated in TME aggravated clinical symptoms and delayed resolution of the disease. Mechanistically, IND reduced arginase activity as well as NO and reactive oxygen species production in MDSCs differentiated in TME but not in TFME. Moreover, expression of the C/EBP-ß transcription factor isoforms correlated with the suppressive activity of IND-treated MDSCs. Our study unveils the dual and context-dependent action of IND, a drug that serves both as an anti-inflammatory and anticancer agent, which differentially affects MDSC activity whether these cells are derived from TME or TFME. These results have broad clinical implication in cancer, chronic inflammation and autoimmunity.
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Antiinflamatorios no Esteroideos/farmacología , Microambiente Celular/efectos de los fármacos , Microambiente Celular/inmunología , Indometacina/farmacología , Células Mieloides/efectos de los fármacos , Células Mieloides/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Animales , Autoinmunidad/efectos de los fármacos , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Inmunofenotipificación , Ratones , Modelos Biológicos , Células Mieloides/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Óxido Nítrico/metabolismo , Fenotipo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/inmunologíaRESUMEN
Bidirectional cross-talk between the neuroendocrine and immune systems orchestrates immune responses in both physiologic and pathologic settings. In this study, we provide in vivo evidence of a critical role for the thyroid hormone triiodothyronine (T3) in controlling the maturation and antitumor functions of dendritic cells (DC). We used a thyroid hormone receptor (TR) ß mutant mouse (TRßPV) to establish the relevance of the T3-TRß system in vivo. In this model, TRß signaling endowed DCs with the ability to stimulate antigen-specific cytotoxic T-cell responses during tumor development. T3 binding to TRß increased DC viability and augmented DC migration to lymph nodes. Moreover, T3 stimulated the ability of DCs to cross-present antigens and to stimulate cytotoxic T-cell responses. In a B16-OVA mouse model of melanoma, vaccination with T3-stimulated DCs inhibited tumor growth and prolonged host survival, in part by promoting the generation of IFNγ-producing CD8(+) T cells. Overall, our results establish an adjuvant effect of T3-TRß signaling in DCs, suggesting an immediately translatable method to empower DC vaccination approaches for cancer immunotherapy.
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Células Dendríticas/inmunología , Melanoma Experimental/inmunología , Receptores beta de Hormona Tiroidea/metabolismo , Triyodotironina/metabolismo , Animales , Linfocitos T CD8-positivos/inmunología , Movimiento Celular , Supervivencia Celular , Reactividad Cruzada , Citotoxicidad Inmunológica , Femenino , Inmunoterapia , Ganglios Linfáticos/inmunología , Melanoma Experimental/terapia , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Astrocytes have complex roles in health and disease, thus it is important to study the pathways that regulate their function. Here we report that lactosylceramide (LacCer) synthesized by ß-1,4-galactosyltransferase 6 (B4GALT6) is upregulated in the central nervous system (CNS) of mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer in astrocytes controls the recruitment and activation of microglia and CNS-infiltrating monocytes in a non-cell autonomous manner by regulating production of the chemokine CCL2 and granulocyte-macrophage colony-stimulating factor (GM-CSF), respectively. We also detected high B4GALT6 gene expression and LacCer concentrations in CNS MS lesions. Inhibition of LacCer synthesis in mice suppressed local CNS innate immunity and neurodegeneration in EAE and interfered with the activation of human astrocytes in vitro. Thus, B4GALT6 regulates astrocyte activation and is a potential therapeutic target for MS and other neuroinflammatory disorders.
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Astrocitos/inmunología , Astrocitos/metabolismo , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Galactosiltransferasas/metabolismo , Glucolípidos/metabolismo , Animales , Antígenos CD/metabolismo , Sistema Nervioso Central/patología , Quimiocina CCL2/genética , Encefalomielitis Autoinmune Experimental/genética , Femenino , Galactosiltransferasas/genética , Técnicas de Silenciamiento del Gen , Proteína Ácida Fibrilar de la Glía , Humanos , Inmunidad Innata , Lactosilceramidos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Transgénicos , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Degeneración Nerviosa/genética , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Regulación hacia ArribaRESUMEN
Intact interleukin-10 receptor (IL-10R) signaling on effector and T regulatory (Treg) cells are each independently required to maintain immune tolerance. Here we show that IL-10 sensing by innate immune cells, independent of its effects on T cells, was critical for regulating mucosal homeostasis. Following wild-type (WT) CD4(+) T cell transfer, Rag2(-/-)Il10rb(-/-) mice developed severe colitis in association with profound defects in generation and function of Treg cells. Moreover, loss of IL-10R signaling impaired the generation and function of anti-inflammatory intestinal and bone-marrow-derived macrophages and their ability to secrete IL-10. Importantly, transfer of WT but not Il10rb(-/-) anti-inflammatory macrophages ameliorated colitis induction by WT CD4(+) T cells in Rag2(-/-)Il10rb(-/-) mice. Similar alterations in the generation and function of anti-inflammatory macrophages were observed in IL-10R-deficient patients with very early onset inflammatory bowel disease. Collectively, our studies define innate immune IL-10R signaling as a key factor regulating mucosal immune homeostasis in mice and humans.
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Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Interleucina-10/inmunología , Receptores de Interleucina-10/inmunología , Traslado Adoptivo , Animales , Diferenciación Celular/inmunología , Proliferación Celular , Células Cultivadas , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Humanos , Tolerancia Inmunológica/genética , Tolerancia Inmunológica/inmunología , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-10/deficiencia , Receptores de Interleucina-10/genética , Transducción de Señal/inmunología , Linfocitos T Reguladores/inmunologíaRESUMEN
Interleukin (IL)-22 produced by innate lymphoid cells (ILCs) and CD4+ T cells plays an important role in host defence and mucosal homeostasis, thus it is important to investigate the mechanisms that regulate IL-22 production. We investigated the regulation IL-22 production by CD4+ T cells. Here we show that IL-21 triggers IL-22, but not IL-17 production by CD4+ T cells. STAT3, activated by IL-21, controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR). Moreover, IL-21 and AhR signalling in T cells control IL-22 production and the development of dextran sodium sulphate-induced colitis in ILC-deficient mice. Thus, we have identified IL-21 as an inducer of IL-22 production in CD4+ T cells in vitro and in vivo.
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Linfocitos T CD4-Positivos/metabolismo , Interleucinas/biosíntesis , Interleucinas/fisiología , Perfilación de la Expresión Génica , Humanos , Interleucinas/genética , Interleucinas/metabolismo , Regiones Promotoras Genéticas , Receptores de Hidrocarburo de Aril/metabolismo , Factor de Transcripción STAT3/fisiología , Transcripción Genética , Interleucina-22RESUMEN
The clinical benefit conferred by vascular endothelial growth factors (VEGF)-targeted therapies is variable, and tumors from treated patients eventually reinitiate growth. Here, we identify a glycosylation-dependent pathway that compensates for the absence of cognate ligand and preserves angiogenesis in response to VEGF blockade. Remodeling of the endothelial cell (EC) surface glycome selectively regulated binding of galectin-1 (Gal1), which upon recognition of complex N-glycans on VEGFR2, activated VEGF-like signaling. Vessels within anti-VEGF-sensitive tumors exhibited high levels of α2-6-linked sialic acid, which prevented Gal1 binding. In contrast, anti-VEGF refractory tumors secreted increased Gal1 and their associated vasculature displayed glycosylation patterns that facilitated Gal1-EC interactions. Interruption of ß1-6GlcNAc branching in ECs or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of α2-6-linked sialic acid conferred resistance to anti-VEGF. Disruption of the Gal1-N-glycan axis promoted vascular remodeling, immune cell influx and tumor growth inhibition. Thus, targeting glycosylation-dependent lectin-receptor interactions may increase the efficacy of anti-VEGF treatment.
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Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias/irrigación sanguínea , Neoplasias/tratamiento farmacológico , Neovascularización Patológica , Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Células Endoteliales/metabolismo , Galectina 1/genética , Galectina 1/metabolismo , Glicosilación , Humanos , Hipoxia , Ratones , Receptores Mitogénicos/metabolismoRESUMEN
Dendritic cells (DCs) control the balance between effector T cells and regulatory T cells in vivo. Hence, the study of DCs might identify mechanisms of disease pathogenesis and guide new therapeutic approaches for disorders mediated by the immune system. We found that interleukin 27 (IL-27) signaling in mouse DCs limited the generation of effector cells of the TH1 and TH17 subsets of helper T cells and the development of experimental autoimmune encephalomyelitis (EAE). The effects of IL-27 were mediated at least in part through induction of the immunoregulatory molecule CD39 in DCs. IL-27-induced CD39 decreased the extracellular concentration of ATP and downregulated nucleotide-dependent activation of the NLRP3 inflammasome. Finally, therapeutic vaccination with IL-27-conditioned DCs suppressed established relapsing-remitting EAE. Thus, IL-27 signaling in DCs limited pathogenic T cell responses and the development of autoimmunity.
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Antígenos CD/genética , Apirasa/genética , Autoinmunidad , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Interleucina-17/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Animales , Anticuerpos/inmunología , Presentación de Antígeno/efectos de los fármacos , Presentación de Antígeno/inmunología , Antígenos CD/metabolismo , Apirasa/metabolismo , Autoanticuerpos/inmunología , Autoinmunidad/efectos de los fármacos , Proteínas Portadoras/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Citocinas/biosíntesis , Células Dendríticas/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Ratones , Ratones Noqueados , Vaina de Mielina/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores de Interleucina , Transducción de Señal , Subgrupos de Linfocitos T/citología , Transcripción Genética/efectos de los fármacosRESUMEN
Inflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS.
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Encefalomielitis Autoinmune Experimental/inmunología , Galectina 1/inmunología , Antígenos Comunes de Leucocito/metabolismo , Microglía/inmunología , Animales , Astrocitos/metabolismo , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiopatología , Quimiocina CCL2/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/terapia , Femenino , Galectina 1/metabolismo , Galectina 1/uso terapéutico , Humanos , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/citología , Microglía/metabolismo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/fisiopatología , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Polisacáridos/metabolismo , Unión Proteica , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
In the present work we aimed at identifying ERα in the plasma membrane of normal anterior pituitary cells and investigated if 17ß-estradiol was able to induce their subcellular redistribution. Our results show that about 8% of anterior pituitary cells expressed ERα in the plasma membrane, with the geometrical mean fluorescence intensity being increased after steroid hormone treatment. 17ß-Estradiol and the selective ERα agonist PPT induced an increase of ERα expression in the plasma membrane and activated the PKCα/ERK 1/2 pathway in a time-course not compatible with genomic actions, thus supporting the notion of membrane-initiated effects. These findings suggest that 17ß-estradiol stimulates the translocation of endogenous ERα to the plasma membrane, consequently modulating this ER pool and leading to cellular biological effects in normal anterior pituitary gland.
Asunto(s)
Membrana Celular/efectos de los fármacos , Estradiol/farmacología , Receptor alfa de Estrógeno/metabolismo , Adenohipófisis/efectos de los fármacos , Animales , Membrana Celular/metabolismo , Células Cultivadas , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Ligandos , Fenoles , Adenohipófisis/citología , Adenohipófisis/metabolismo , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Transporte de Proteínas/efectos de los fármacos , Pirazoles/farmacología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Regulación hacia ArribaRESUMEN
Considering that estradiol is a major modulator of prolactin (PRL) secretion, the aim of the present study was to analyze the role of membrane estradiol receptor-α (mERα) in the regulatory effect of this hormone on the PRL secretion induced by thyrotropin-releasing hormone (TRH) by focusing on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway activation. Anterior pituitary cell cultures from female rats were treated with 17ß-estradiol (E(2), 10 nM) and its membrane-impermeable conjugated estradiol (E(2)-BSA, 10 nM) alone or coincubated with TRH (10 nM) for 30 min, with PRL levels being determined by RIA. Although E(2), E(2)-BSA, TRH, and E(2)/TRH differentially increased the PRL secretion, the highest levels were achieved with E(2)-BSA/TRH. ICI-182,780 did not modify the TRH-induced PRL release but significantly inhibited the PRL secretion promoted by E(2) or E(2)-BSA alone or in coincubation with TRH. The PI3K inhibitors LY-294002 and wortmannin partially inhibited the PRL release induced by E(2)-BSA, TRH, and E(2)/TRH and totally inhibited the PRL levels stimulated by E(2)-BSA/TRH, suggesting that the mER mediated the cooperative effect of E(2) on TRH-induced PRL release through the PI3K pathway. Also, the involvement of this kinase was supported by the translocation of its regulatory subunit p85α from the cytoplasm to the plasma membrane in the lactotroph cells treated with E(2)-BSA and TRH alone or in coincubation. A significant increase of phosphorylated Akt was induced by E(2)-BSA/TRH. Finally, the changes of ERα expression in the plasmalemma of pituitary cells were examined by confocal microscopy and flow cytometry, which revealed that the mobilization of intracellular ERα to the plasma membrane of lactotroph cells was only induced by E(2). These finding showed that E(2) may act as a modulator of the secretory response of lactotrophs induced by TRH through mER, with the contribution by PI3K/Akt pathway activation providing a new insight into the mechanisms underlying the nongenomic action of E(2) in the pituitary.
Asunto(s)
Estradiol/farmacología , Receptor alfa de Estrógeno/metabolismo , Adenohipófisis , Prolactina/metabolismo , Transducción de Señal/fisiología , Hormona Liberadora de Tirotropina/metabolismo , Animales , Membrana Celular/metabolismo , Células Cultivadas , Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Femenino , Proteínas de la Membrana/metabolismo , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Adenohipófisis/citología , Adenohipófisis/efectos de los fármacos , Adenohipófisis/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Albúmina Sérica Bovina/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Glucocorticoids (GCs) are widely used as anti-inflammatory and immunosuppressive agents. Several studies have indicated the important role of dendritic cells (DCs), highly specialized antigen-presenting and immunomodulatory cells, in GC-mediated suppression of adaptive immune responses. Recently, we demonstrated that triiodothyronine (T3) has potent immunostimulatory effects on bone marrow-derived mouse DCs through a mechanism involving T3 binding to cytosolic thyroid hormone receptor (TR) ß1, rapid and sustained Akt activation and IL-12 production. Here we explored the impact of GCs on T3-mediated DC maturation and function and the intracellular events underlying these effects. Dexamethasone (Dex), a synthetic GC, potently inhibited T3-induced stimulation of DCs by preventing the augmented expression of maturation markers and the enhanced IL-12 secretion through mechanisms involving the GC receptor. These effects were accompanied by increased IL-10 levels following exposure of T3-conditioned DCs to Dex. Accordingly, Dex inhibited the immunostimulatory capacity of T3-matured DCs on naive T-cell proliferation and IFN-γ production while increased IL-10 synthesis by allogeneic T cell cultures. A mechanistic analysis revealed the ability of Dex to dampen T3 responses through modulation of Akt phosphorylation and cytoplasmic-nuclear shuttling of nuclear factor-κB (NF-κB). In addition, Dex decreased TRß1 expression in both immature and T3-maturated DCs through mechanisms involving the GC receptor. Thus GCs, which are increased during the resolution of inflammatory responses, counteract the immunostimulatory effects of T3 on DCs and their ability to polarize adaptive immune responses toward a T helper (Th)-1-type through mechanisms involving, at least in part, NF-κB- and TRß1-dependent pathways. Our data provide an alternative mechanism for the anti-inflammatory effects of GCs with critical implications in immunopathology at the cross-roads of the immune-endocrine circuits.
Asunto(s)
Inmunidad Adaptativa/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Dexametasona/farmacología , Glucocorticoides/farmacología , Receptores de Glucocorticoides/metabolismo , Receptores de Hormona Tiroidea/metabolismo , Triyodotironina/farmacología , Adyuvantes Inmunológicos/antagonistas & inhibidores , Adyuvantes Inmunológicos/metabolismo , Adyuvantes Inmunológicos/farmacología , Animales , Biomarcadores/análisis , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Células Cultivadas , Células Dendríticas/citología , Células Dendríticas/inmunología , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-10/biosíntesis , Interleucina-10/inmunología , Interleucina-12/biosíntesis , Interleucina-12/inmunología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/inmunología , FN-kappa B/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/inmunología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Glucocorticoides/inmunología , Receptores de Hormona Tiroidea/inmunología , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Triyodotironina/antagonistas & inhibidores , Triyodotironina/metabolismoRESUMEN
In spite of their central role in orchestrating immunity, dendritic cells (DCs) can also limit harmful reactions and promote immune tolerance by inducing T cell anergy or favoring the differentiation of T regulatory (T(reg)) cells. Several factors may influence the 'decision' of DCs to become immunogenic or tolerogenic including the nature of antigenic challenge, the engagement of selective pathogen recognition receptors (PRRs) and the balance of cytokines and growth factors. In addition, mounting evidence indicates a key role of endogenous lectins including C-type lectins, siglecs and galectins in shaping DC immunogenicity and tailoring adaptive immune responses, through recognition of specific 'glycan signatures' on invading pathogens or host cells. While galectins are in general secreted proteins that act in a paracrine or autocrine manner, all known siglecs and most C-type lectins are membrane-bound receptors that convey glycan-containing information into DC differentiation or maturation programs. Yet, some of the signaling pathways triggered by endogenous lectins converge in similar functional outcomes regardless of divergences in their structure, homology or glycan-binding specificity. To gain a more complete understanding on the role of protein-glycan interactions in DC biology, here we will integrate scattered information on these structurally-divergent but functionally-related lectins and their potential biomedical applications.
Asunto(s)
Células Dendríticas/inmunología , Galectinas/inmunología , Inmunoterapia , Lectinas Tipo C/inmunología , Lectinas/inmunología , Inmunidad Adaptativa , Animales , Tecnología Biomédica , Comunicación Celular , Humanos , Tolerancia Inmunológica , Inmunoterapia/tendencias , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , Transducción de SeñalRESUMEN
Effective immunity relies on the recognition of pathogens and tumors by innate immune cells through diverse pattern recognition receptors (PRRs) that lead to initiation of signaling processes and secretion of pro- and anti-inflammatory cytokines. Galectins, a family of endogenous lectins widely expressed in infected and neoplastic tissues have emerged as part of the portfolio of soluble mediators and pattern recognition receptors responsible for eliciting and controlling innate immunity. These highly conserved glycan-binding proteins can control immune cell processes through binding to specific glycan structures on pathogens and tumors or by acting intracellularly via modulation of selective signaling pathways. Recent findings demonstrate that various galectin family members influence the fate and physiology of different innate immune cells including polymorphonuclear neutrophils, mast cells, macrophages, and dendritic cells. Moreover, several pathogens may actually utilize galectins as a mechanism of host invasion. In this review, we aim to highlight and integrate recent discoveries that have led to our current understanding of the role of galectins in host-pathogen interactions and innate immunity. Challenges for the future will embrace the rational manipulation of galectin-glycan interactions to instruct and shape innate immunity during microbial infections, inflammation, and cancer.