RESUMEN
Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.
Asunto(s)
Colitis/patología , Dieta , Intestinos/patología , Oxazoles/farmacología , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Colitis/inducido químicamente , Colitis/metabolismo , Modelos Animales de Enfermedad , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interleucina-10/metabolismo , Intestinos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células T Asesinas Naturales/inmunología , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/genética , Triptófano/metabolismoRESUMEN
The induction of type I interferons by the bacterial secondary messengers cyclic di-GMP (c-di-GMP) or cyclic di-AMP (c-di-AMP) is dependent on a signaling axis that involves the adaptor STING, the kinase TBK1 and the transcription factor IRF3. Here we identified the heliase DDX41 as a pattern-recognition receptor (PRR) that sensed both c-di-GMP and c-di-AMP. DDX41 specifically and directly interacted with c-di-GMP. Knockdown of DDX41 via short hairpin RNA in mouse or human cells inhibited the induction of genes encoding molecules involved in the innate immune response and resulted in defective activation of STING, TBK1 and IRF3 in response to c-di-GMP or c-di-AMP. Our results suggest a mechanism whereby c-di-GMP and c-di-AMP are detected by DDX41, which forms a complex with STING to signal to TBK1-IRF3 and activate the interferon response.
Asunto(s)
GMP Cíclico/análogos & derivados , ARN Helicasas DEAD-box/metabolismo , Fosfatos de Dinucleósidos/metabolismo , Interferón Tipo I/inmunología , Listeria monocytogenes/inmunología , Listeria monocytogenes/metabolismo , Receptores de Reconocimiento de Patrones/metabolismo , Animales , Línea Celular , GMP Cíclico/metabolismo , ARN Helicasas DEAD-box/genética , Humanos , Inmunidad Innata , Factor 3 Regulador del Interferón/metabolismo , Macrófagos/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Receptores de Reconocimiento de Patrones/genética , Sistemas de Mensajero Secundario , Transducción de SeñalRESUMEN
Nlrp3 inflammasome activation occurs in response to numerous agonists but the specific mechanism by which this takes place remains unclear. All previously evaluated activators of the Nlrp3 inflammasome induce the generation of mitochondrial reactive oxygen species (ROS), suggesting a model in which ROS is a required upstream mediator of Nlrp3 inflammasome activation. Here we have identified the oxazolidinone antibiotic linezolid as a Nlrp3 agonist that activates the Nlrp3 inflammasome independently of ROS. The pathways for ROS-dependent and ROS-independent Nlrp3 activation converged upon mitochondrial dysfunction and specifically the mitochondrial lipid cardiolipin. Cardiolipin bound to Nlrp3 directly and interference with cardiolipin synthesis specifically inhibited Nlrp3 inflammasome activation. Together these data suggest that mitochondria play a critical role in the activation of the Nlrp3 inflammasome through the direct binding of Nlrp3 to cardiolipin.
Asunto(s)
Cardiolipinas/metabolismo , Proteínas Portadoras/metabolismo , Inflamasomas/metabolismo , Mitocondrias/metabolismo , Acetamidas/metabolismo , Acetamidas/farmacología , Animales , Cardiolipinas/inmunología , Línea Celular , Ciclosporina/metabolismo , Activación Enzimática , Humanos , Inflamación/inducido químicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Linezolid , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Mitocondrias/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR , Oxazolidinonas/metabolismo , Oxazolidinonas/farmacología , Potasio/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Invariant NKT (iNKT) cells have the unique ability to shape immunity during antitumor immune responses and other forms of sterile and nonsterile inflammation. Recent studies have highlighted a variety of classes of endogenous and pathogen-derived lipid antigens that can trigger iNKT cell activation under sterile and nonsterile conditions. However, the context and mechanisms that drive the presentation of self-lipid antigens in sterile inflammation remain unclear. Here we report that endoplasmic reticulum (ER)-stressed myeloid cells, via signaling events modulated by the protein kinase RNA-like ER kinase (PERK) pathway, increase CD1d-mediated presentation of immunogenic endogenous lipid species, which results in enhanced iNKT cell activation both in vitro and in vivo. In addition, we demonstrate that actin cytoskeletal reorganization during ER stress results in an altered distribution of CD1d on the cell surface, which contributes to enhanced iNKT cell activation. These results define a previously unidentified mechanism that controls iNKT cell activation during sterile inflammation.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Células Dendríticas/inmunología , Estrés del Retículo Endoplásmico/inmunología , Activación de Linfocitos , Células T Asesinas Naturales/inmunología , Animales , Presentación de Antígeno , Antígenos CD1d/biosíntesis , Antígenos CD1d/inmunología , Autoantígenos/inmunología , Carcinoma Pulmonar de Lewis/patología , Línea Celular Tumoral , Técnicas de Cocultivo , Citoesqueleto/ultraestructura , Endosomas/inmunología , Glicoesfingolípidos/inmunología , Glicoesfingolípidos/metabolismo , Humanos , Subunidad alfa del Receptor de Interleucina-2/biosíntesis , Lípidos/inmunología , Lisosomas/inmunología , Ratones , Ratones Endogámicos C57BL , Células THP-1 , Tapsigargina/farmacología , Respuesta de Proteína Desplegada/inmunología , eIF-2 Quinasa/deficiencia , eIF-2 Quinasa/fisiologíaRESUMEN
Neurotrauma especially traumatic brain injury (TBI) is the leading cause of death and disability worldwide. To improve upon the early diagnosis and develop precision-targeted therapies for TBI, it is critical to understand the underlying molecular mechanisms and signaling pathways. The transcription factor, nuclear factor kappa B (NFκB), which is ubiquitously expressed, plays a crucial role in the normal cell survival, proliferation, differentiation, function, as well as in disease states like neuroinflammation and neurodegeneration. Here, we hypothesized that real-time noninvasive bioluminescence molecular imaging allows rapid and precise monitoring of TBI-induced immediate and rapid spatio-temporal activation of NFκB signaling pathway in response to Glia maturation factor (GMF) upregulation which in turn leads to neuroinflammation and neurodegeneration post-TBI. To test and validate our hypothesis and to gain novel mechanistic insights, we subjected NFκB-RE-Luc transgenic male and female mice to TBI and performed real-time noninvasive bioluminescence imaging (BLI) as well as photoacoustic and ultrasound imaging (PAI). Our BLI data revealed that TBI leads to an immediate and sustained activation of NFκB signaling. Further, our BLI data suggest that especially in male NFκB-RE-Luc transgenic mice subjected to TBI, in addition to brain, there is widespread activation of NFκB signaling in multiple organs. However, in the case of the female NFκB-RE-Luc transgenic mice, TBI induces a very specific and localized activation of NFκB signaling in the brain. Further, our microRNA data suggest that TBI induces significant upregulation of mir-9-5p, mir-21a-5p, mir-34a-5p, mir-16-3p, as well as mir-155-5p within 24 h and these microRNAs can be successfully used as TBI-specific biomarkers. To the best of our knowledge, this is one of the first and unique study of its kind to report immediate and sustained activation of NFκB signaling post-TBI in a gender-specific manner by utilizing real-time non-invasive BLI and PAI in NFκB-RE-Luc transgenic mice. Our study will prove immensely beneficial to gain novel mechanistic insights underlying TBI, unravel novel therapeutic targets, as well as enable us to monitor in real-time the response to innovative TBI-specific precision-targeted gene and stem cell-based precision medicine.
Asunto(s)
Lesiones Traumáticas del Encéfalo/metabolismo , Factor de Maduración de la Glia/metabolismo , Mediciones Luminiscentes/métodos , FN-kappa B/metabolismo , Técnicas Fotoacústicas/métodos , Caracteres Sexuales , Ultrasonografía Intervencional/métodos , Animales , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Sistemas de Computación , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones TransgénicosRESUMEN
The molecular mechanism mediating degeneration of nigrostriatal dopaminergic neurons in Parkinson's disease (PD) is not yet fully understood. Previously, we have shown the contribution of glia maturation factor (GMF), a proinflammatory protein in dopaminergic neurodegeneration mediated by activation of mast cells (MCs). In this study, methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal neurodegeneration and astro-glial activations were determined by western blot and immunofluorescence techniques in wild type (WT) mice, MC-deficient (MC-KO) mice and GMF-deficient (GMF-KO) mice, with or without MC reconstitution before MPTP administration. We show that GMF-KO in the MCs reduces the synergistic effects of MC and Calpain1 (calcium-activated cysteine protease enzyme)-dependent dopaminergic neuronal loss that reduces motor behavioral impairments in MPTP-treated mouse. Administration of MPTP increase in calpain-mediated proteolysis in nigral dopaminergic neurons further resulting in motor decline in mice. We found that MPTP administered WT mice exhibits oxidative stress due to significant increases in the levels of malondialdehyde, superoxide dismutase and reduction in the levels of reduced glutathione and glutathione peroxidase activity as compared with both MC-KO and GMF-KO mice. The number of TH-positive neurons in the ventral tegmental area, substantia nigra and the fibers in the striatum were significantly reduced while granulocyte macrophage colony-stimulating factor (GM-CSF), MC-Tryptase, GFAP, IBA1, Calpain1 and intracellular adhesion molecule 1 expression were significantly increased in WT mice. Similarly, tyrosine hydroxylase, dopamine transporters and vesicular monoamine transporters 2 proteins expression were significantly reduced in the SN of MPTP treated WT mice. The motor behavior as analyzed by rotarod and hang test was significantly reduced in WT mice as compared with both the MC-KO and GMF-KO mice. We conclude that GMF-dependent MC activation enhances the detrimental effect of astro-glial activation-mediated oxidative stress and neuroinflammation in the midbrain, and its inhibition may slowdown the progression of PD.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Neuronas Dopaminérgicas/metabolismo , Factor de Maduración de la Glia , Microglía/metabolismo , Animales , Modelos Animales de Enfermedad , Dopamina , Factor de Maduración de la Glia/metabolismo , Mastocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Sustancia Negra/metabolismoRESUMEN
The NLRP3 inflammasome is activated in response to microbial and danger signals, resulting in caspase-1-dependent secretion of the proinflammatory cytokines IL-1ß and IL-18. Canonical NLRP3 inflammasome activation is a two-step process requiring both priming and activation signals. During inflammasome activation, NLRP3 associates with mitochondria; however, the role for this interaction is unclear. In this article, we show that mouse NLRP3 and caspase-1 independently interact with the mitochondrial lipid cardiolipin, which is externalized to the outer mitochondrial membrane at priming in response to reactive oxygen species. An NLRP3 activation signal is then required for the calcium-dependent association of the adaptor molecule ASC with NLRP3 on the mitochondrial surface, resulting in inflammasome complex assembly and activation. These findings demonstrate a novel lipid interaction for caspase-1 and identify a role for mitochondria as supramolecular organizing centers in the assembly and activation of the NLRP3 inflammasome.
Asunto(s)
Cardiolipinas/metabolismo , Caspasa 1/metabolismo , Inflamasomas/metabolismo , Mitocondrias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Cardiolipinas/inmunología , Caspasa 1/inmunología , Inflamasomas/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunologíaRESUMEN
Traumatic brain injury (TBI) is one of the major health problems worldwide that causes death or permanent disability through primary and secondary damages in the brain. TBI causes primary brain damage and activates glial cells and immune and inflammatory cells, including mast cells in the brain associated with neuroinflammatory responses that cause secondary brain damage. Though the survival rate and the neurological deficiencies have shown significant improvement in many TBI patients with newer therapeutic options, the underlying pathophysiology of TBI-mediated neuroinflammation, neurodegeneration, and cognitive dysfunctions is understudied. In this study, we analyzed mast cells and neuroinflammation in weight drop-induced TBI. We analyzed mast cell activation by toluidine blue staining, serum chemokine C-C motif ligand 2 (CCL2) level by enzyme-linked immunosorbent assay (ELISA), and proteinase-activated receptor-2 (PAR-2), a mast cell and inflammation-associated protein, vascular endothelial growth factor receptor 2 (VEGFR2), and blood-brain barrier tight junction-associated claudin 5 and Zonula occludens-1 (ZO-1) protein expression in the brains of TBI mice. Mast cell activation and its numbers increased in the brains of 24 h and 72 h TBI when compared with sham control brains without TBI. Mouse brains after TBI show increased CCL2, PAR-2, and VEGFR2 expression and derangement of claudin 5 and ZO-1 expression as compared with sham control brains. TBI can cause mast cell activation, neuroinflammation, and derangement of tight junction proteins associated with increased BBB permeability. We suggest that inhibition of mast cell activation can suppress neuroimmune responses and glial cell activation-associated neuroinflammation and neurodegeneration in TBI.
Asunto(s)
Lesiones Traumáticas del Encéfalo/inmunología , Lesiones Traumáticas del Encéfalo/metabolismo , Mastocitos/metabolismo , Proteínas de Uniones Estrechas/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Lesiones Encefálicas/metabolismo , Quimiocina CCL2/sangre , Claudina-5/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor PAR-2/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Proteína de la Zonula Occludens-1/metabolismoRESUMEN
Stimulator of interferon genes (STING) is an important regulator of the innate immune response to cytoplasmic DNA. However, regulation of STING itself is largely unknown. Here, we show that STING transcription is induced by innate immune activators, such as cyclic dinucleotides (CDNs), through an IFNAR1- and STAT1-dependent pathway. We also identify a STAT1 binding site in the STING promoter that contributes to the activation of STING transcription. Furthermore, we show that induction of STING mediates the positive feedback regulation of CDN-triggered IFN-I. Thus, our study demonstrates that STING is an interferon-stimulated gene (ISG) and its induction is crucial for the IFN-I positive feedback loop.
Asunto(s)
Interferón Tipo I/metabolismo , Interferones/metabolismo , Proteínas de la Membrana/metabolismo , Animales , Sitios de Unión , Línea Celular , Inmunidad Innata/genética , Interferón Tipo I/genética , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/metabolismo , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismoRESUMEN
Rapid and robust induction of type I IFN (IFN-I) is a critical event in host antiviral innate immune response. It has been well demonstrated that cyclic GMP-AMP (cGAMP) synthase (cGAS) plays an important role in sensing cytosolic DNA and triggering STING dependent signaling to induce IFN-I. However, it is largely unknown how cGAS itself is regulated during pathogen infection and IFN-I production. In this study, we show that pattern recognition receptor (PRR) ligands, including lipid A, LPS, poly(I:C), poly(dA:dT), and cGAMP, induce cGAS expression in an IFN-I-dependent manner in both mouse and human macrophages. Further experiments indicated that cGAS is an IFN-stimulated gene (ISG), and two adjacent IFN-sensitive response elements (ISREs) in the promoter region of cGAS mediate the induction of cGAS by IFN-I. Additionally, we show that optimal production of IFN-ß triggered by poly (dA:dT) or HSV-1 requires IFNAR signaling. Knockdown of the constitutively expressed DNA sensor DDX41 attenuates poly(dA:dT)-triggered IFN-ß production and cGAS induction. By analyzing the dynamic expression of poly(dA:dT)-induced IFN-ß and cGAS transcripts, we have found that induction of IFN-ß is earlier than cGAS. Furthermore, we have provided evidence that induction of cGAS by IFN-I meditates the subsequent positive feedback regulation of DNA-triggered IFN-I production. Thus, our study not only provides a novel mechanism of modulating cGAS expression, but also adds another layer of regulation in DNA-triggered IFN-I production by induction of cGAS.
Asunto(s)
Inmunidad Innata/inmunología , Interferón Tipo I/biosíntesis , Macrófagos/inmunología , Nucleotidiltransferasas/inmunología , Animales , Línea Celular , Inmunoprecipitación de Cromatina , Ensayo de Inmunoadsorción Enzimática , Retroalimentación Fisiológica , Humanos , Immunoblotting , Interferón Tipo I/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nucleotidiltransferasas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Expression of MHC class I molecules, which provide immune surveillance against intracellular pathogens, is higher on lymphoid cells than on any other cell types. In T cells, this is a result of activation of class I transcription by the T cell enhanceosome consisting of Runx1, CBFß, and LEF1. We now report that MHC class I transcription in T cells also is enhanced by Foxp3, resulting in higher levels of class I in CD4(+)CD25(+) T regulatory cells than in conventional CD4(+)CD25(-) T cells. Interestingly, the effect of Foxp3 regulation of MHC class I transcription is cell type specific: Foxp3 increases MHC class I expression in T cells but represses it in epithelial tumor cells. In both cell types, Foxp3 targets the upstream IFN response element and downstream core promoter of the class I gene. Importantly, expression of MHC class I contributes to the function of CD4(+)CD25(+) T regulatory cells by enhancing immune suppression, both in in vitro and in vivo. These findings identify MHC class I genes as direct targets of Foxp3 whose expression augments regulatory T cell function.
Asunto(s)
Factores de Transcripción Forkhead/inmunología , Regulación de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Linfocitos T Reguladores/inmunología , Animales , Secuencia de Bases , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Células HeLa , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Células Jurkat , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Transgénicos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Ácido Nucleico , Linfocitos T Reguladores/metabolismo , Timocitos/inmunología , Timocitos/metabolismo , Microglobulina beta-2/deficiencia , Microglobulina beta-2/genética , Microglobulina beta-2/inmunologíaRESUMEN
UNLABELLED: Viral infections are often linked to altered drug metabolism in patients; however, the underlying molecular mechanisms remain unclear. Here we describe a mechanism by which activation of antiviral responses by the synthetic double-stranded RNA ligand, polyinosinic-polycytidylic acid (polyI:C), leads to decreased acetaminophen (APAP) metabolism and hepatotoxicity. PolyI:C administration down-regulates expression of retinoic X receptor-α (RXRα) as well as its heterodimeric partner pregnane X receptor (PXR) in mice. This down-regulation results in suppression of downstream cytochrome P450 enzymes involved in conversion of APAP to its toxic metabolite. Although the effects of polyI:C on drug metabolism are often attributed to interferon production, we report that polyI:C can decrease APAP metabolism in the absence of the type I interferon receptor. Furthermore, we demonstrate that polyI:C can attenuate APAP metabolism through both its membrane-bound receptor, Toll-like receptor 3 (TLR3), as well as cytoplasmic receptors. CONCLUSION: This is the first study to illustrate that in vivo administration of polyI:C affects drug metabolism independent of type I interferon production or in the absence of TLR3 through crosstalk between nuclear receptors and antiviral responses.
Asunto(s)
Acetaminofén/efectos adversos , Antivirales/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Interferón Tipo I/metabolismo , Poli I-C/uso terapéutico , Receptor Toll-Like 3/metabolismo , Acetaminofén/metabolismo , Animales , Antivirales/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Sinergismo Farmacológico , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Poli I-C/farmacología , Receptor X de Pregnano , ARN Bicatenario/farmacología , ARN Viral/genética , Receptores de Esteroides/metabolismo , Receptor alfa X Retinoide/metabolismo , Xenobióticos/farmacología , Xenobióticos/uso terapéuticoRESUMEN
Dying cells are capable of activating the innate immune system and inducing a sterile inflammatory response. Here, we show that necrotic cells are sensed by the Nlrp3 inflammasome resulting in the subsequent release of the proinflammatory cytokine IL-1beta. Necrotic cells produced by pressure disruption, hypoxic injury, or complement-mediated damage were capable of activating the Nlrp3 inflammasome. Nlrp3 inflammasome activation was triggered in part through ATP produced by mitochondria released from damaged cells. Neutrophilic influx into the peritoneum in response to necrotic cells in vivo was also markedly diminished in the absence of Nlrp3. Nlrp3-deficiency moreover protected animals against mortality, renal dysfunction, and neutrophil influx in an in vivo renal ischemic acute tubular necrosis model. These findings suggest that the inhibition of Nlrp3 inflammasome activity can diminish the acute inflammation and damage associated with tissue injury.
Asunto(s)
Proteínas Portadoras/inmunología , Inflamación/inmunología , Necrosis/inmunología , Adenosina Trifosfato/metabolismo , Animales , Proteínas Portadoras/metabolismo , Ensayo de Inmunoadsorción Enzimática , Proteínas de la Matriz Extracelular/metabolismo , Interleucina-1beta/inmunología , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLRRESUMEN
Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1beta and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis.
Asunto(s)
Proteínas Portadoras/metabolismo , Inflamación/inmunología , Silicosis/inmunología , Silicosis/patología , Administración por Inhalación , Animales , Proteínas Reguladoras de la Apoptosis , Amianto/administración & dosificación , Amianto/farmacología , Proteínas Adaptadoras de Señalización CARD , Colágeno/metabolismo , Proteínas del Citoesqueleto/deficiencia , Proteínas del Citoesqueleto/inmunología , Citotoxicidad Inmunológica/efectos de los fármacos , Endocitosis/efectos de los fármacos , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR , Potasio/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Acute traumatic brain injury (TBI) leads to neuroinflammation, neurodegeneration, cognitive decline, psychological disorders, increased blood-brain barrier (BBB) permeability, and microvascular damage in the brain. Inflammatory mediators secreted from activated glial cells, neurons, and mast cells are implicated in the pathogenesis of TBI through secondary brain damage. Abnormalities or damage to the neurovascular unit is the indication of secondary injuries in the brain after TBI. However, the precise mechanisms of molecular and ultrastructural neurovascular alterations involved in the pathogenesis of acute TBI are not yet clearly understood. Moreover, currently, there are no precision-targeted effective treatment options to prevent the sequelae of TBI. In this study, mice were subjected to closed head weight-drop-induced acute TBI and evaluated neuroinflammatory and neurovascular alterations in the brain by immunofluorescence staining or quantitation by enzyme-linked immunosorbent assay (ELISA) procedure. Mast cell stabilizer drug cromolyn was administered to inhibit the neuroinflammatory response of TBI. Results indicate decreased level of pericyte marker platelet-derived growth factor receptor-beta (PDGFR-ß) and BBB-associated tight junction proteins junctional adhesion molecule-A (JAM-A) and zonula occludens-1 (ZO-1) in the brains 7 days after weight-drop-induced acute TBI as compared with the brains from sham control mice indicating acute TBI-associated BBB/tight junction protein disruption. Further, the administration of cromolyn drug significantly inhibited acute TBI-associated decrease of PDGFR-ß, JAM-A, and ZO-1 in the brain. These findings suggest that acute TBI causes BBB/tight junction damage and that cromolyn administration could protect this acute TBI-induced brain damage as well as its long-time consequences.
Asunto(s)
Lesiones Traumáticas del Encéfalo/metabolismo , Encéfalo/metabolismo , Trastornos Cerebrovasculares/metabolismo , Encefalitis/metabolismo , Animales , Encéfalo/irrigación sanguínea , Lesiones Traumáticas del Encéfalo/complicaciones , Trastornos Cerebrovasculares/etiología , Encefalitis/etiología , Masculino , Ratones , Neuronas/metabolismoRESUMEN
Neuroinflammation leads to neurodegeneration, cognitive defects, and neurodegenerative disorders. Neurotrauma/traumatic brain injury (TBI) can cause activation of glial cells, neurons, and neuroimmune cells in the brain to release neuroinflammatory mediators. Neurotrauma leads to immediate primary brain damage (direct damage), neuroinflammatory responses, neuroinflammation, and late secondary brain damage (indirect) through neuroinflammatory mechanism. Secondary brain damage leads to chronic inflammation and the onset and progression of neurodegenerative diseases. Currently, there are no effective and specific therapeutic options to treat these brain damages or neurodegenerative diseases. Flavone luteolin is an important natural polyphenol present in several plants that show anti-inflammatory, antioxidant, anticancer, cytoprotective, and macrophage polarization effects. In this short review article, we have reviewed the neuroprotective effects of luteolin in neurotrauma and neurodegenerative disorders and pathways involved in this mechanism. We have collected data for this study from publications in the PubMed using the keywords luteolin and mast cells, neuroinflammation, neurodegenerative diseases, and TBI. Recent reports suggest that luteolin suppresses systemic and neuroinflammatory responses in Coronavirus disease 2019 (COVID-19). Studies have shown that luteolin exhibits neuroprotective effects through various mechanisms, including suppressing immune cell activation, such as mast cells, and inflammatory mediators released from these cells. In addition, luteolin can suppress neuroinflammatory response, activation of microglia and astrocytes, oxidative stress, neuroinflammation, and the severity of neuroinflammatory diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and TBI pathogenesis. In conclusion, luteolin can improve cognitive decline and enhance neuroprotection in neurodegenerative diseases, TBI, and stroke.
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Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Tratamiento Farmacológico de COVID-19 , Inflamación/tratamiento farmacológico , Luteolina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/virología , Lesiones Encefálicas/complicaciones , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/virología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/virología , COVID-19/complicaciones , COVID-19/virología , Flavonas/uso terapéutico , Humanos , Inflamación/complicaciones , Inflamación/virología , Neuronas/efectos de los fármacos , Neuronas/virología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/patogenicidadRESUMEN
PURPOSE: Psychological stress is a significant health problem in veterans and their family members. Traumatic brain injury (TBI) and stress lead to the onset, progression, and worsening of several inflammatory and neurodegenerative diseases in veterans and civilians. Alzheimer's disease (AD) is a progressive, irreversible neuroinflammatory disease that causes problems with memory, thinking, and behavior. TBIs and chronic psychological stress cause and accelerate the pathology of neuroinflammatory diseases such as AD. However, the precise molecular and cellular mechanisms governing neuroinflammation and neurodegeneration are currently unknown, especially in veterans. The purpose of this review article was to advance the hypothesis that stress and TBI-mediated immune response substantially contribute and accelerate the pathogenesis of AD in veterans and their close family members and civilians. METHODS: The information in this article was collected and interpreted from published articles in PubMed between 1985 and 2020 using the key words stress, psychological stress, Afghanistan war, Operation Enduring Freedom (OEF), Iraq War, Operation Iraqi Freedom (OIF), Operation New Dawn (OND), traumatic brain injury, mast cell and stress, stress and neuroimmune response, stress and Alzheimer's disease, traumatic brain injury, and Alzheimer's disease. FINDINGS: Chronic psychological stress and brain injury induce the generation and accumulation of beta-amyloid peptide, amyloid plaques, neurofibrillary tangles, and phosphorylation of tau in the brain, thereby contributing to AD pathogenesis. Active military personnel and veterans are under enormous psychological stress due to various war-related activities, including TBIs, disabilities, fear, new environmental conditions, lack of normal life activities, insufficient communications, explosions, military-related noise, and health hazards. Brain injury, stress, mast cell, and other immune cell activation can induce headache, migraine, dementia, and upregulate neuroinflammation and neurodegeneration in veterans of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn. TBIs, posttraumatic stress disorder, psychological stress, pain, glial activation, and dementia in active military personnel, veterans, or their family members can cause AD several years later in their lives. We suggest that there are increasing numbers of veterans with TBIs and stress and that these veterans may develop AD late in life if no appropriate therapeutic intervention is available. IMPLICATIONS: Per these published reports, the fact that TBIs and psychological stress can accelerate the pathogenesis of AD should be recognized. Active military personnel, veterans, and their close family members should be evaluated regularly for stress symptoms to prevent the pathogenesis of neurodegenerative diseases, including AD.
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Campaña Afgana 2001- , Enfermedad de Alzheimer/epidemiología , Lesiones Encefálicas/epidemiología , Guerra de Irak 2003-2011 , Estrés Psicológico/epidemiología , Veteranos/psicología , Enfermedad de Alzheimer/inmunología , Lesiones Encefálicas/inmunología , Humanos , Estrés Psicológico/inmunologíaRESUMEN
Traumatic brain injury (TBI) is a major health problem in the United States, which affects about 1.7 million people each year. Glial cells, T-cells, and mast cells perform specific protective functions in different regions of the brain for the recovery of cognitive and motor functions after central nervous system (CNS) injuries including TBI. Chronic neuroinflammatory responses resulting in neuronal death and the accompanying stress following brain injury predisposes or accelerates the onset and progression of Alzheimer's disease (AD) in high-risk individuals. About 5.7 million Americans are currently living with AD. Immediately following brain injury, mast cells respond by releasing prestored and preactivated mediators and recruit immune cells to the CNS. Blood-brain barrier (BBB), tight junction and adherens junction proteins, neurovascular and gliovascular microstructural rearrangements, and dysfunction associated with increased trafficking of inflammatory mediators and inflammatory cells from the periphery across the BBB leads to increase in the chronic neuroinflammatory reactions following brain injury. In this review, we advance the hypothesis that neuroinflammatory responses resulting from mast cell activation along with the accompanying risk factors such as age, gender, food habits, emotional status, stress, allergic tendency, chronic inflammatory diseases, and certain drugs can accelerate brain injury-associated neuroinflammation, neurodegeneration, and AD pathogenesis.
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Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Lesiones Traumáticas del Encéfalo/fisiopatología , Encéfalo/metabolismo , Inflamación/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/fisiopatologíaRESUMEN
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new pandemic infectious disease that originated in China. COVID-19 is a global public health emergency of international concern. COVID-19 causes mild to severe illness with high morbidity and mortality, especially in preexisting risk groups. Therapeutic options are now limited to COVID-19. The hallmark of COVID-19 pathogenesis is the cytokine storm with elevated levels of interleukin-6 (IL-6), IL-1ß, tumor necrosis factor-alpha (TNF-α), chemokine (C-C-motif) ligand 2 (CCL2), and granulocyte-macrophage colony-stimulating factor (GM-CSF). COVID-19 can cause severe pneumonia, and neurological disorders, including stroke, the damage to the neurovascular unit, blood-brain barrier disruption, high intracranial proinflammatory cytokines, and endothelial cell damage in the brain. Mast cells are innate immune cells and also implicated in adaptive immune response, systemic inflammatory diseases, neuroinflammatory diseases, traumatic brain injury and stroke, and stress disorders. SARS-CoV-2 can activate monocytes/macrophages, dendritic cells, T cells, mast cells, neutrophils, and induce cytokine storm in the lung. COVID-19 can activate mast cells, neurons, glial cells, and endothelial cells. SARS-CoV-2 infection can cause psychological stress and neuroinflammation. In conclusion, COVID-19 can induce mast cell activation, psychological stress, cytokine storm, and neuroinflammation.