RESUMO
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.
Assuntos
Colite/patologia , Dieta , Intestinos/patologia , Oxazóis/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interleucina-10/metabolismo , Intestinos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Triptofano/metabolismoRESUMO
Microbes constitute the very core of our existence. Long believed to be a nuisance and proponents of various disease, latest research point toward their functions in processes that can prove beneficial for human survival and afford long-term protection from disease. The wide range of functions exhibited by a host of microbes implies diversity and heterogeneity at the level of the molecular machinery, thus stressing the need to take a closer look at the molecular underpinnings that dictate distinct outcomes.
Assuntos
Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Interação Gene-Ambiente , Genética Microbiana , Interações Hospedeiro-Patógeno , Imunidade/genética , Estresse Fisiológico , Bactérias/classificação , Evolução Molecular , Genoma Bacteriano , HumanosRESUMO
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.
Assuntos
GMP Cíclico/análogos & derivados , RNA Helicases DEAD-box/metabolismo , Fosfatos de Dinucleosídeos/metabolismo , Interferon Tipo I/imunologia , Listeria monocytogenes/imunologia , Listeria monocytogenes/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Animais , Linhagem Celular , GMP Cíclico/metabolismo , RNA Helicases DEAD-box/genética , Humanos , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno , Receptores de Reconhecimento de Padrão/genética , Sistemas do Segundo Mensageiro , Transdução de SinaisRESUMO
Satisfactory function, esthetics, and phonetics together with long-term stability and minimal complications are all considered as metrics that define a successful outcome. The current case report is documentation of a mandibular subperiosteal implant with a successful follow-up of 56 years. Numerous issues can be credited for the long-term successful outcome including selection of the patient, heedfulness of basic anatomic and physiologic principles, design of the implant and superstructure, surgical execution, application of sound restorative principles, conscientious hygiene, and clockwork recare. The case demonstrates intense cooperation and coordination among the surgeon, restorative dentist, and laboratory technical staff, together with long-lasting patient compliance. Execution of the treatment with a mandibular subperiosteal implant helped this patient overcome the status of a dental cripple. The highlight of the case is that it is the longest success ever documented in the history of any type of implant treatment.
Assuntos
Implantes Dentários , Humanos , Estética Dentária , Mandíbula/cirurgia , Prótese Dentária Fixada por Implante , Revestimento de DentaduraRESUMO
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.
Assuntos
Cardiolipinas/metabolismo , Proteínas de Transporte/metabolismo , Inflamassomos/metabolismo , Mitocôndrias/metabolismo , Acetamidas/metabolismo , Acetamidas/farmacologia , Animais , Cardiolipinas/imunologia , Linhagem Celular , Ciclosporina/metabolismo , Ativação Enzimática , Humanos , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Linezolida , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Mitocôndrias/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Oxazolidinonas/metabolismo , Oxazolidinonas/farmacologia , Potássio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Dendríticas/imunologia , Estresse do Retículo Endoplasmático/imunologia , Ativação Linfocitária , Células T Matadoras Naturais/imunologia , Animais , Apresentação de Antígeno , Antígenos CD1d/biossíntese , Antígenos CD1d/imunologia , Autoantígenos/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Citoesqueleto/ultraestrutura , Endossomos/imunologia , Glicoesfingolipídeos/imunologia , Glicoesfingolipídeos/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Lipídeos/imunologia , Lisossomos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células THP-1 , Tapsigargina/farmacologia , Resposta a Proteínas não Dobradas/imunologia , eIF-2 Quinase/deficiência , eIF-2 Quinase/fisiologiaRESUMO
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.
Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Fator de Maturação da Glia/metabolismo , Medições Luminescentes/métodos , NF-kappa B/metabolismo , Técnicas Fotoacústicas/métodos , Caracteres Sexuais , Ultrassonografia de Intervenção/métodos , Animais , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Sistemas Computacionais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos TransgênicosRESUMO
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.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Neurônios Dopaminérgicos/metabolismo , Fator de Maturação da Glia , Microglia/metabolismo , Animais , Modelos Animais de Doenças , Dopamina , Fator de Maturação da Glia/metabolismo , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Substância Negra/metabolismoRESUMO
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.
Assuntos
Cardiolipinas/metabolismo , Caspase 1/metabolismo , Inflamassomos/metabolismo , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Cardiolipinas/imunologia , Caspase 1/imunologia , Inflamassomos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologiaRESUMO
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.
Assuntos
Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/metabolismo , Mastócitos/metabolismo , Proteínas de Junções Íntimas/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/metabolismo , Quimiocina CCL2/sangue , Claudina-5/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor PAR-2/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
Invariant natural killer T (iNKT) cells recognize lipid antigens presented by CD1d and play a central role in regulating immunity and inflammation in peripheral tissues. However, the mechanisms which govern iNKT cell homeostasis after thymic emigration are incompletely understood. Here we demonstrate that microsomal triglyceride transfer protein (MTP), a protein involved in the transfer of lipids onto CD1d, regulates liver iNKT cell homeostasis in a manner dependent on hepatocyte CD1d. Mice with hepatocyte-specific loss of MTP exhibit defects in the function of CD1d and show increased hepatic iNKT cell numbers as a consequence of altered iNKT cell apoptosis. Similar findings were made in mice with hepatocyte-specific loss of CD1d, confirming a critical role of CD1d in this process. Moreover, increased hepatic iNKT cell abundance in the absence of MTP is associated with susceptibility to severe iNKT cell-mediated hepatitis, thus demonstrating the importance of CD1d-dependent control of liver iNKT cells in maintaining immunological homeostasis in the liver. Together, these data demonstrate an unanticipated role of parenchymal cells, as shown here for hepatocytes, in tissue-specific regulation of CD1d-restricted immunity and further suggest that alterations in lipid metabolism may affect iNKT cell homeostasis through effects on CD1d-associated lipid antigens.
Assuntos
Antígenos CD1d/imunologia , Proteínas de Transporte/imunologia , Hepatócitos/imunologia , Tolerância Imunológica/imunologia , Células T Matadoras Naturais/imunologia , Animais , Antígenos CD1d/genética , Apoptose/imunologia , Proteínas de Transporte/genética , Feminino , Inflamação/imunologia , Fígado/imunologia , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
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.
Assuntos
Interferon Tipo I/metabolismo , Interferons/metabolismo , Proteínas de Membrana/metabolismo , Animais , Sítios de Ligação , Linhagem Celular , Imunidade Inata/genética , Interferon Tipo I/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas/genética , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismoRESUMO
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.
Assuntos
Imunidade Inata/imunologia , Interferon Tipo I/biossíntese , Macrófagos/imunologia , Nucleotidiltransferases/imunologia , Animais , Linhagem Celular , Imunoprecipitação da Cromatina , Ensaio de Imunoadsorção Enzimática , Retroalimentação Fisiológica , Humanos , Immunoblotting , Interferon Tipo I/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nucleotidiltransferases/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that, in early hypertension, the susceptibility to stress-induced VT/VF increases. We compared the susceptibility of 5- to 6-month-old male spontaneously hypertensive rats (SHR) and age/sex-matched normotensive rats (NR) to VT/VF during challenge with oxidative stress (H2 O2 ; 0.15 mmol l(-1) ). We found that only SHR hearts exhibited left ventricular fibrosis and hypertrophy. H2 O2 promoted VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage-calcium optical mapping of Langendorff-perfused SHR hearts revealed that H2 O2 -induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)-mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR ventricular myocytes, except with larger EAD amplitude. During the early stages of hypertension, when challenged with oxidative stress, SHR hearts showed an increased ventricular arrhythmogenicity that stems primarily from tissue remodelling (hypertrophy, fibrosis) rather than cellular electrophysiological changes. Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.
Assuntos
Hipertensão/fisiopatologia , Taquicardia Ventricular/fisiopatologia , Potenciais de Ação , Animais , Células Cultivadas , Fibrose , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hipertensão/complicações , Masculino , Ratos , Ratos Wistar , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/patologiaRESUMO
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.
Assuntos
Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Linfócitos T Reguladores/imunologia , Animais , Sequência de Bases , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citometria de Fluxo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células HeLa , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Células Jurkat , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência do Ácido Nucleico , Linfócitos T Reguladores/metabolismo , Timócitos/imunologia , Timócitos/metabolismo , Microglobulina beta-2/deficiência , Microglobulina beta-2/genética , Microglobulina beta-2/imunologiaRESUMO
Takotsubo cardiomyopathy, also called transient left ventricular apical ballooning syndrome or Gebrochenes-Herz-Syndrome, is a rare entity which may masquerade as acute coronary syndrome (ACS) with sudden onset of chest pain and/or dyspnea, transient left ventricle apical akinesia, electrocardiographic changes typical of ACS and mild increase in cardiac enzymes in the background of normal coronary arteries. Here, we present a case of a 45 year old female who presented with acute onset dyspnea and chest pain with severe ischemic changes on the ECG and raised troponin levels. She was treated with a provisional diagnosis of an ACS but on further workup was found to have Takotsubo cardiomyopathy. Her presentation to the hospital along with relevant clinical findings, electrocardiographic, echocardiographic and angiographic findings are presented in the article.
Assuntos
Síndrome Coronariana Aguda/diagnóstico , Cardiomiopatia de Takotsubo/diagnóstico , Dor no Peito , Diagnóstico Diferencial , Ecocardiografia , Eletrocardiografia , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Iatrogenic injury to the maxillary sinus membrane is a common complication during direct sinus lift procedures. The most common cause is perforation of the Schneiderian membrane using a tungsten-carbide round bur no.6. We propose a safe technique in which an acrylic stone trimmer is used to create a window in the maxillary antrum thereby minimizing the risk of injury to the delicate sinus membrane.
Assuntos
Complicações Intraoperatórias/prevenção & controle , Mucosa Nasal/lesões , Levantamento do Assoalho do Seio Maxilar/instrumentação , Idoso , Substitutos Ósseos/uso terapêutico , Colágeno , Desenho de Equipamento , Feminino , Humanos , Doença Iatrogênica , Seio Maxilar/cirurgia , Membranas Artificiais , Minerais/uso terapêutico , Osteotomia/instrumentação , Segurança do Paciente , Levantamento do Assoalho do Seio Maxilar/métodos , Retalhos Cirúrgicos/cirurgiaRESUMO
Alveolar ridge resorption accelerates following extraction of teeth and the residual defect varies from socket to socket. This article proposes a new treatment oriented classification of extraction defects. It also reviews several graft materials and membranes that aid in the decision for selecting an appropriate socket preservation technique. The algorithm developed by the authors helps design a potentially successful treatment plan based on the classification of extraction defects, with choices ranging from no treatment to complex grafting procedures (i.e. allogenic block grafts). In addition, the principles of wound healing and the ideal time points for utilizing the various types of graft materials and implants are discussed. This socket preservation treatment algorithm will guide clinicians to employ surgical procedures using various biomaterials to promote a successful outcome.