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1.
Cell ; 176(3): 581-596.e18, 2019 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-30661753

RESUMEN

Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.


Asunto(s)
Astrocitos/metabolismo , Sistema Nervioso Central/metabolismo , Animales , Sistema Nervioso Central/inmunología , Biología Computacional/métodos , Encefalomielitis Autoinmune Experimental/inmunología , Endorribonucleasas/metabolismo , Ambiente , Exposición a Riesgos Ambientales/efectos adversos , Genoma , Genómica , Humanos , Inflamación/metabolismo , Linurona/efectos adversos , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores sigma/efectos de los fármacos , Receptores sigma/metabolismo , Transducción de Señal , Proteína 1 de Unión a la X-Box/metabolismo , Pez Cebra
2.
Cell ; 179(7): 1483-1498.e22, 2019 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-31813625

RESUMEN

Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Astrocitos/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Fosfolipasas A2 Secretoras/metabolismo , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/farmacología , 1-Desoxinojirimicina/uso terapéutico , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Encéfalo/metabolismo , Encéfalo/patología , Células Cultivadas , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Femenino , Hexoquinasa/metabolismo , Humanos , Ácido Láctico/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Fosfolipasas A2 Secretoras/genética
3.
Nature ; 627(8005): 865-872, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38509377

RESUMEN

Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis1-8 (EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge. Specifically, using a combination of single-cell RNA sequencing, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, focused interrogation of cells by nucleic acid detection and sequencing, and cell-specific in vivo CRISPR-Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP-citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) that is used by histone acetyltransferase p300 to control chromatin accessibility. The number of ACLY+p300+ memory astrocytes is increased in acute and chronic EAE models, and their genetic inactivation ameliorated EAE. We also detected the pro-inflammatory memory phenotype in human astrocytes in vitro; single-cell RNA sequencing and immunohistochemistry studies detected increased numbers of ACLY+p300+ astrocytes in chronic multiple sclerosis lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, multiple sclerosis. These findings may guide novel therapeutic approaches for multiple sclerosis and other neurologic diseases.


Asunto(s)
Astrocitos , Encefalomielitis Autoinmune Experimental , Memoria Epigenética , Esclerosis Múltiple , Animales , Femenino , Humanos , Masculino , Ratones , Acetilcoenzima A/metabolismo , Astrocitos/enzimología , Astrocitos/metabolismo , Astrocitos/patología , ATP Citrato (pro-S)-Liasa/metabolismo , Cromatina/genética , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina , Secuenciación de Inmunoprecipitación de Cromatina , Sistemas CRISPR-Cas , Encefalomielitis Autoinmune Experimental/enzimología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Inflamación/enzimología , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Esclerosis Múltiple/enzimología , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Análisis de Expresión Génica de una Sola Célula , Transposasas/metabolismo
4.
Nature ; 620(7975): 881-889, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37558878

RESUMEN

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.


Asunto(s)
Enfermedades Autoinmunes , Sistema Nervioso Central , Células Dendríticas , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ácido Láctico , Humanos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/prevención & control , Autoinmunidad , Sistema Nervioso Central/citología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ácido Láctico/metabolismo , Probióticos/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/inmunología , Retroalimentación Fisiológica , Lactasa/genética , Lactasa/metabolismo , Análisis de la Célula Individual
5.
Nature ; 611(7937): 801-809, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36266581

RESUMEN

Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)1-a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2. However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPß signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases.


Asunto(s)
Ambiente , Herbicidas , Inflamación , Enfermedades Inflamatorias del Intestino , Intestinos , Animales , Ratones , Inflamación/inducido químicamente , Inflamación/etiología , Inflamación/inmunología , Inflamación/patología , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Pez Cebra , Aprendizaje Automático , Bases de Datos Factuales , Modelos Animales de Enfermedad , Intestinos/efectos de los fármacos , Intestinos/inmunología , Intestinos/metabolismo , Intestinos/patología , FN-kappa B , Proteína beta Potenciadora de Unión a CCAAT , Receptores de Hidrocarburo de Aril , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Herbicidas/efectos adversos
7.
Nature ; 557(7707): 724-728, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29769726

RESUMEN

Microglia and astrocytes modulate inflammation and neurodegeneration in the central nervous system (CNS)1-3. Microglia modulate pro-inflammatory and neurotoxic activities in astrocytes, but the mechanisms involved are not completely understood4,5. Here we report that TGFα and VEGF-B produced by microglia regulate the pathogenic activities of astrocytes in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis. Microglia-derived TGFα acts via the ErbB1 receptor in astrocytes to limit their pathogenic activities and EAE development. Conversely, microglial VEGF-B triggers FLT-1 signalling in astrocytes and worsens EAE. VEGF-B and TGFα also participate in the microglial control of human astrocytes. Furthermore, expression of TGFα and VEGF-B in CD14+ cells correlates with the multiple sclerosis lesion stage. Finally, metabolites of dietary tryptophan produced by the commensal flora control microglial activation and TGFα and VEGF-B production, modulating the transcriptional program of astrocytes and CNS inflammation through a mechanism mediated by the aryl hydrocarbon receptor. In summary, we identified positive and negative regulators that mediate the microglial control of astrocytes. Moreover, these findings define a pathway through which microbial metabolites limit pathogenic activities of microglia and astrocytes, and suppress CNS inflammation. This pathway may guide new therapies for multiple sclerosis and other neurological disorders.


Asunto(s)
Astrocitos/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/microbiología , Microglía/metabolismo , Animales , Astrocitos/patología , Células Cultivadas , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/microbiología , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/prevención & control , Receptores ErbB/metabolismo , Femenino , Humanos , Inflamación/metabolismo , Inflamación/microbiología , Inflamación/patología , Inflamación/prevención & control , Receptores de Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Receptores de Hidrocarburo de Aril/metabolismo , Simbiosis , Factor de Crecimiento Transformador alfa/biosíntesis , Factor de Crecimiento Transformador alfa/metabolismo , Triptófano/deficiencia , Triptófano/metabolismo , Factor B de Crecimiento Endotelial Vascular/biosíntesis , Factor B de Crecimiento Endotelial Vascular/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo
8.
J Neurochem ; 158(1): 25-35, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-32402091

RESUMEN

Sphingolipids are a class of lipids highly enriched in the central nervous system (CNS), which shows great diversity and complexity, and has been implicated in CNS development and function. Alterations in sphingolipid metabolism have been described in multiple diseases, including those affecting the central nervous system (CNS). In this review, we discuss the role of sphingolipid metabolism in neurodegeneration, evaluating its direct roles in neuron development and health, and also in the induction of neurotoxic activities in CNS-resident astrocytes and microglia in the context of neurologic diseases such as multiple sclerosis and Alzheimer's disease. Finally, we focus on the metabolism of gangliosides and sphingosine-1-phosphate, its contribution to the pathogenesis of neurologic diseases, and its potential as a candidate target for the therapeutic modulation of neurodegeneration.


Asunto(s)
Enfermedades Neurodegenerativas/metabolismo , Esfingolípidos/metabolismo , Animales , Enfermedades del Sistema Nervioso Central/metabolismo , Gangliósidos/metabolismo , Humanos , Metabolismo de los Lípidos , Lisofosfolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo
9.
Proc Natl Acad Sci U S A ; 114(8): 2012-2017, 2017 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-28167760

RESUMEN

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.


Asunto(s)
Astrocitos/efectos de los fármacos , Inmunosupresores/farmacología , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Receptores de Lisoesfingolípidos/metabolismo , Animales , Astrocitos/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/patología , Femenino , Clorhidrato de Fingolimod/farmacología , Clorhidrato de Fingolimod/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Microglía/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Esclerosis Múltiple Crónica Progresiva/patología , Cultivo Primario de Células , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato , Transcriptoma/efectos de los fármacos
10.
Eukaryot Cell ; 12(6): 804-15, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23543673

RESUMEN

The CCAAT motif is ubiquitous in promoters of eukaryotic genomes. The CCAAT-binding complex (CBC) is conserved across a wide range of organisms, specifically recognizes the CCAAT motif, and modulates transcription directly or in cooperation with other transcription factors. In Candida albicans, CBC is known to interact with the repressor Hap43 to negatively regulate iron utilization genes in response to iron deprivation. However, the extent of additional functions of CBC is unclear. In this study, we explored new roles of CBC in C. albicans and found that CBC pleiotropically regulates many virulence traits in vitro, including negative control of genes responsible for ribosome biogenesis and translation and positive regulation of low-nitrogen-induced filamentation. In addition, C. albicans CBC is involved in utilization of host proteins as nitrogen sources and in repression of cellular flocculation and adhesin gene expression. Moreover, our epistasis analyses suggest that CBC acts as a downstream effector of Rhb1-TOR signaling and controls low-nitrogen-induced filamentation via the Mep2-Ras1-protein kinase A (PKA)/mitogen-activated protein kinase (MAPK) pathway. Importantly, the phenotypes identified here are all independent of Hap43. Finally, deletion of genes encoding CBC components slightly attenuated C. albicans virulence in both zebrafish and murine models of infection. Our results thus highlight new roles of C. albicans CBC in regulating multiple virulence traits in response to environmental perturbations and, finally, suggest potential targets for antifungal therapies as well as extending our understanding of the pathogenesis of other fungal pathogens.


Asunto(s)
Factor de Unión a CCAAT/genética , Candida albicans/genética , Candida albicans/patogenicidad , Proteínas Fúngicas/genética , Regulación Fúngica de la Expresión Génica , Animales , Factor de Unión a CCAAT/metabolismo , Candida albicans/metabolismo , Candidiasis/microbiología , Candidiasis/mortalidad , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Proteínas Fúngicas/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Hierro/metabolismo , Ratones , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mutación , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal , Análisis de Supervivencia , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Virulencia , Pez Cebra , Proteínas ras/genética , Proteínas ras/metabolismo
11.
bioRxiv ; 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38260616

RESUMEN

Astrocytes play important roles in the central nervous system (CNS) physiology and pathology. Indeed, astrocyte subsets defined by specific transcriptional activation states contribute to the pathology of neurologic diseases, including multiple sclerosis (MS) and its pre-clinical model experimental autoimmune encephalomyelitis (EAE) 1-8 . However, little is known about the stability of these disease-associated astrocyte subsets, their regulation, and whether they integrate past stimulation events to respond to subsequent challenges. Here, we describe the identification of an epigenetically controlled memory astrocyte subset which exhibits exacerbated pro-inflammatory responses upon re-challenge. Specifically, using a combination of single-cell RNA sequencing (scRNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), and cell-specific in vivo CRISPR/Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) used by the histone acetyltransferase p300 to control chromatin accessibility. ACLY + p300 + memory astrocytes are increased in acute and chronic EAE models; the genetic targeting of ACLY + p300 + astrocytes using CRISPR/Cas9 ameliorated EAE. We also detected responses consistent with a pro-inflammatory memory phenotype in human astrocytes in vitro ; scRNA-seq and immunohistochemistry studies detected increased ACLY + p300 + astrocytes in chronic MS lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, MS. These findings may guide novel therapeutic approaches for MS and other neurologic diseases.

12.
Alcohol Clin Exp Res (Hoboken) ; 47(5): 856-867, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36871955

RESUMEN

BACKGROUND AND PURPOSE: Gut bacteria metabolize tryptophan into indoles. Intestinal levels of the tryptophan metabolite indole-3-acetic acid are reduced in patients with alcohol-associated hepatitis. Supplementation of indole-3-acetic acid protects against ethanol-induced liver disease in mice. The aim of this study was to evaluate the effect of engineered bacteria producing indoles as Aryl-hydrocarbon receptor (Ahr) agonists. METHODS: C57BL/6 mice were subjected to chronic-plus-binge ethanol feeding and orally given PBS, control Escherichia coli Nissle 1917 (EcN) or engineered EcN-Ahr. The effects of EcN and EcN-Ahr were also examined in mice lacking Ahr in interleukin 22 (Il22)-producing cells. RESULTS: Through the deletion of endogenous genes trpR and tnaA, coupled with overexpression of a feedback-resistant tryptophan biosynthesis operon, EcN-Ahr were engineered to overproduce tryptophan. Additional engineering allowed conversion of this tryptophan to indoles including indole-3-acetic acid and indole-3-lactic acid. EcN-Ahr ameliorated ethanol-induced liver disease in C57BL/6 mice. EcN-Ahr upregulated intestinal gene expression of Cyp1a1, Nrf2, Il22, Reg3b, and Reg3g, and increased Il22-expressing type 3 innate lymphoid cells. In addition, EcN-Ahr reduced translocation of bacteria to the liver. The beneficial effect of EcN-Ahr was abrogated in mice lacking Ahr expression in Il22-producing immune cells. CONCLUSIONS: Our findings indicate that tryptophan metabolites locally produced by engineered gut bacteria mitigate liver disease via Ahr-mediated activation in intestinal immune cells.

13.
bioRxiv ; 2023 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-36993446

RESUMEN

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1α. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1α/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.

14.
BMC Bioinformatics ; 12 Suppl 1: S17, 2011 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-21342546

RESUMEN

BACKGROUND: Signal transduction is the major mechanism through which cells transmit external stimuli to evoke intracellular biochemical responses. Understanding relationship between external stimuli and corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach to integrate experimental data and qualitative knowledge to identify the physiological consequences of environmental stimuli is needed. RESULTS: In present study, we employed a genetic algorithm-based Boolean model to represent NF-κB signaling pathway. We were able to capture feedback and crosstalk characteristics to enhance our understanding on the acute and chronic inflammatory response. Key network components affecting the response dynamics were identified. CONCLUSIONS: We designed an effective algorithm to elucidate the process of immune response using comprehensive knowledge about network structure and limited experimental data on dynamic responses. This approach can potentially be implemented for large-scale analysis on cellular processes and organism behaviors.


Asunto(s)
Algoritmos , Inflamación/metabolismo , Modelos Biológicos , FN-kappa B/metabolismo , Transducción de Señal , Inflamación/inmunología , FN-kappa B/inmunología , Receptor Cross-Talk
15.
Artículo en Inglés | MEDLINE | ID: mdl-33408169

RESUMEN

OBJECTIVE: MS is an autoimmune demyelinating disease of the CNS, which causes neurologic deficits in young adults and leads to progressive disability. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, can drive anti-inflammatory functions in peripheral immune cells and also in CNS-resident cells. Laquinimod is a drug developed for the treatment of MS known to activate AHR, but the cellular targets of laquinimod are still not completely known. In this work, we analyzed the contribution of AHR activation in astrocytes to its beneficial effects in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS. METHODS: We used conditional knockout mice, in combination with genome-wide analysis of gene expression by RNA-seq and in vitro culture systems to investigate the effects of laquinimod on astrocytes. RESULTS: We found that AHR activation in astrocytes by laquinimod ameliorates EAE, a preclinical model of MS. Genome-wide RNA-seq transcriptional analyses detected anti-inflammatory effects of laquinimod in glial cells during EAE. Moreover, we established that the Delaq metabolite of laquinimod dampens proinflammatory mediator production while activating tissue-protective mechanisms in glia. CONCLUSIONS: Taken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.


Asunto(s)
Astrocitos/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/prevención & control , Quinolonas/uso terapéutico , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/inmunología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Quinolonas/farmacología , Receptores de Hidrocarburo de Aril/inmunología
16.
Science ; 372(6540)2021 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-33888612

RESUMEN

Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.


Asunto(s)
Astrocitos/fisiología , Comunicación Celular , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Microglía/fisiología , Esclerosis Múltiple/fisiopatología , Análisis de la Célula Individual , Animales , Antígenos CD/metabolismo , Encéfalo/patología , Encéfalo/fisiopatología , Sistema Nervioso Central/fisiopatología , Encefalomielitis Autoinmune Experimental/patología , Efrina-B3/metabolismo , Herpesvirus Suido 1/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Esclerosis Múltiple/patología , FN-kappa B/metabolismo , Proteínas del Tejido Nervioso/metabolismo , RNA-Seq , Especies Reactivas de Oxígeno/metabolismo , Receptor EphB3/antagonistas & inhibidores , Receptor EphB3/metabolismo , Receptores de Superficie Celular/metabolismo , Semaforinas/metabolismo , Transducción de Señal , Linfocitos T/fisiología , Serina-Treonina Quinasas TOR/metabolismo
17.
BMC Bioinformatics ; 11: 308, 2010 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-20529327

RESUMEN

BACKGROUND: Signal transduction is the major mechanism through which cells transmit external stimuli to evoke intracellular biochemical responses. Diverse cellular stimuli create a wide variety of transcription factor activities through signal transduction pathways, resulting in different gene expression patterns. Understanding the relationship between external stimuli and the corresponding cellular responses, as well as the subsequent effects on downstream genes, is a major challenge in systems biology. Thus, a systematic approach is needed to integrate experimental data and theoretical hypotheses to identify the physiological consequences of environmental stimuli. RESULTS: We proposed a systematic approach that combines forward and reverse engineering to link the signal transduction cascade with the gene responses. To demonstrate the feasibility of our strategy, we focused on linking the NF-kappaB signaling pathway with the inflammatory gene regulatory responses because NF-kappaB has long been recognized to play a crucial role in inflammation. We first utilized forward engineering (Hybrid Functional Petri Nets) to construct the NF-kappaB signaling pathway and reverse engineering (Network Components Analysis) to build a gene regulatory network (GRN). Then, we demonstrated that the corresponding IKK profiles can be identified in the GRN and are consistent with the experimental validation of the IKK kinase assay. We found that the time-lapse gene expression of several cytokines and chemokines (TNF-alpha, IL-1, IL-6, CXCL1, CXCL2 and CCL3) is concordant with the NF-kappaB activity profile, and these genes have stronger influence strength within the GRN. Such regulatory effects have highlighted the crucial roles of NF-kappaB signaling in the acute inflammatory response and enhance our understanding of the systemic inflammatory response syndrome. CONCLUSION: We successfully identified and distinguished the corresponding signaling profiles among three microarray datasets with different stimuli strengths. In our model, the crucial genes of the NF-kappaB regulatory network were also identified to reflect the biological consequences of inflammation. With the experimental validation, our strategy is thus an effective solution to decipher cross-talk effects when attempting to integrate new kinetic parameters from other signal transduction pathways. The strategy also provides new insight for systems biology modeling to link any signal transduction pathways with the responses of downstream genes of interest.


Asunto(s)
Simulación por Computador , Expresión Génica , Genómica/métodos , Inflamación/genética , FN-kappa B/genética , FN-kappa B/metabolismo , Transducción de Señal/genética , Genoma
18.
Infect Immun ; 78(6): 2512-21, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20308295

RESUMEN

In this work, the zebrafish model organism was developed to obtain a minivertebrate host system for a Candida albicans infection study. We demonstrated that C. albicans can colonize and invade zebrafish at multiple anatomical sites and kill the fish in a dose-dependent manner. Inside zebrafish, we monitored the progression of the C. albicans yeast-to-hypha transition by tracking morphogenesis, and we monitored the corresponding gene expression of the pathogen and the early host immune response. We performed a zebrafish survival assay with different C. albicans strains (SC5314, ATCC 10231, an hgc1 mutant, and a cph1/efg1 double mutant) to determine each strain's virulence, and the results were similar to findings reported in previous mouse model studies. Finally, using zebrafish embryos, we monitored C. albicans infection and visualized the interaction between pathogen and host myelomonocytic cells in vivo. Taken together, the results of this work demonstrate that zebrafish can be a useful host model to study C. albicans pathogenesis, and they highlight the advantages of using the zebrafish model in future invasive fungal research.


Asunto(s)
Candida albicans/patogenicidad , Candidiasis/patología , Modelos Animales de Enfermedad , Animales , Candidiasis/inmunología , Candidiasis/microbiología , Perfilación de la Expresión Génica , Regulación Fúngica de la Expresión Génica , Interacciones Huésped-Patógeno , Hifa/crecimiento & desarrollo , Análisis de Supervivencia , Virulencia , Pez Cebra
19.
Nat Neurosci ; 22(5): 729-740, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30962630

RESUMEN

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 Tumoral
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