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1.
Molecules ; 26(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803783

RESUMO

Inflammasomes are immune cytosolic oligomers involved in the initiation and progression of multiple pathologies and diseases. The tight regulation of these immune sensors is necessary to control an optimal inflammatory response and recover organism homeostasis. Prolonged activation of inflammasomes result in the development of chronic inflammatory diseases, and the use of small drug-like inhibitory molecules are emerging as promising anti-inflammatory therapies. Different aspects have to be taken in consideration when designing inflammasome inhibitors. This review summarizes the different techniques that can be used to study the mechanism of action of potential inflammasome inhibitory molecules.


Assuntos
Inflamassomos/efeitos dos fármacos , Alarminas/imunologia , Alarminas/metabolismo , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Simulação por Computador , Citocinas/metabolismo , Desenho de Fármacos , Humanos , Imunidade Inata , Técnicas Imunológicas , Inflamassomos/imunologia , Inflamassomos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Biológicos , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
2.
Planta ; 253(1): 11, 2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33389186

RESUMO

KEY MESSAGE: We reviewed recent advances related to RIN4, including its involvement in the immune process through posttranslational modifications, PM H+-ATPase activity regulation, interaction with EXO70 and identification of RIN4-associated NLR proteins. RPM1-interacting protein 4 (RIN4) is a conserved plant immunity regulator that has been extensively studied and can be modified by pathogenic effector proteins. RIN4 plays an important role in both PTI and ETI. In this article, we review the functions of the two conserved NOI domains of RIN4, the C-terminal cysteine residues required for membrane localization and the sites targeted and modified by effector proteins during plant immunity. In addition, we discuss the effect of RIN4 on the stomatal virulence of pathogens via the regulation of PM H+-ATPase activity, which is involved in the immune process through interactions with the exocyst subunit EXO70, and progress in the identification of RIN4-related R proteins in multiple species. This review provides new insights enhancing the current understanding of the immune function of RIN4.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Peptídeos e Proteínas de Sinalização Intracelular , Imunidade Vegetal , Arabidopsis/imunologia , Arabidopsis/microbiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Imunidade Vegetal/genética , Estômatos de Plantas/imunologia , Estômatos de Plantas/microbiologia
3.
Mol Cell ; 81(5): 953-968.e9, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33503407

RESUMO

While the role of transcription factors and coactivators in controlling enhancer activity and chromatin structure linked to gene expression is well established, the involvement of corepressors is not. Using inflammatory macrophage activation as a model, we investigate here a corepressor complex containing GPS2 and SMRT both genome-wide and at the Ccl2 locus, encoding the chemokine CCL2 (MCP-1). We report that corepressors co-occupy candidate enhancers along with the coactivators CBP (H3K27 acetylase) and MED1 (mediator) but act antagonistically by repressing eRNA transcription-coupled H3K27 acetylation. Genome editing, transcriptional interference, and cistrome analysis reveals that apparently related enhancer and silencer elements control Ccl2 transcription in opposite ways. 4C-seq indicates that corepressor depletion or inflammatory signaling functions mechanistically similarly to trigger enhancer activation. In ob/ob mice, adipose tissue macrophage-selective depletion of the Ccl2 enhancer-transcribed eRNA reduces metaflammation. Thus, the identified corepressor-eRNA-chemokine pathway operates in vivo and suggests therapeutic opportunities by targeting eRNAs in immuno-metabolic diseases.


Assuntos
Quimiocina CCL2/genética , Proteínas Correpressoras/genética , Elementos Facilitadores Genéticos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Correpressor 2 de Receptor Nuclear/genética , Obesidade/genética , Elementos Silenciadores Transcricionais , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Sistemas CRISPR-Cas , Quimiocina CCL2/imunologia , Proteínas Correpressoras/imunologia , Edição de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Histona Acetiltransferases/genética , Histona Acetiltransferases/imunologia , Histonas/genética , Histonas/imunologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/imunologia , Camundongos , Camundongos Obesos , Correpressor 2 de Receptor Nuclear/imunologia , Obesidade/imunologia , Obesidade/patologia , Células RAW 264.7 , RNA não Traduzido/genética , RNA não Traduzido/imunologia , Transdução de Sinais
4.
BMJ Case Rep ; 14(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431450

RESUMO

An 83-year-old woman was referred to hospital with a 2-week history of short-lived episodic unpleasant sensations in her head and running down her body. This was accompanied by new short-term memory impairment and arm spasms. Initial investigations including blood tests and brain imaging did not reveal the diagnosis. The patient developed an increasing frequency of abnormal movements of her face and arm. These were clinically recognised as faciobrachial dystonic seizures (FBDS). FBDS are pathognomonic of an autoimmune encephalitis caused by an antibody directed against leucine-rich glioma-inactivated 1 (LGI1). The clinical diagnosis resulted in treatment with immunotherapy, leading to cessation of seizures and rapid cognitive recovery. Later, the predicted serology was confirmed. This reversible and under-recognised cause of cognitive impairment, typically affecting elderly patients, can be diagnosed clinically to enable early and effective treatment.


Assuntos
Autoanticorpos/sangue , Disfunção Cognitiva/imunologia , Imunoterapia/métodos , Encefalite Límbica/diagnóstico , Convulsões/imunologia , Administração Intravenosa , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Disfunção Cognitiva/terapia , Feminino , Glucocorticoides/administração & dosagem , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Encefalite Límbica/complicações , Encefalite Límbica/imunologia , Encefalite Límbica/terapia , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/imunologia , Metilprednisolona/administração & dosagem , Troca Plasmática , Tomografia por Emissão de Pósitrons , Convulsões/terapia , Resultado do Tratamento
5.
Clin Nucl Med ; 46(3): 250-251, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33323741

RESUMO

ABSTRACT: We report the case of a 55-year-old man presenting pseudopsychiatric behavior disorders of subacute-onset. MRI showed a FLAIR (fluid-attenuated inversion recovery) hyperintensity in the left hippocampus. The diagnosis of limbic encephalitis was raised, and the patient was referred for an 18F-FDG PET/CT. PET/CT depicted an increased uptake of the left mesiotemporal structures and also an increased uptake of both cerebellum and striatal areas. This pattern was compatible with an anti-leucine-rich glioma-inactivated 1 antibody encephalitis that was later confirmed.


Assuntos
Anticorpos/imunologia , Fluordesoxiglucose F18 , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Encefalite Límbica/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Seguimentos , Humanos , Encefalite Límbica/imunologia , Masculino , Pessoa de Meia-Idade
6.
Nat Commun ; 11(1): 3687, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703941

RESUMO

Microglia, resident immune cells of the CNS, are thought to defend against infections. Toxoplasma gondii is an opportunistic infection that can cause severe neurological disease. Here we report that during T. gondii infection a strong NF-κB and inflammatory cytokine transcriptional signature is overrepresented in blood-derived macrophages versus microglia. Interestingly, IL-1α is enriched in microglia and IL-1ß in macrophages. We find that mice lacking IL-1R1 or IL-1α, but not IL-1ß, have impaired parasite control and immune cell infiltration within the brain. Further, we show that microglia, not peripheral myeloid cells, release IL-1α ex vivo. Finally, we show that ex vivo IL-1α release is gasdermin-D dependent, and that gasdermin-D and caspase-1/11 deficient mice show deficits in brain inflammation and parasite control. These results demonstrate that microglia and macrophages are differently equipped to propagate inflammation, and that in chronic T. gondii infection, microglia can release the alarmin IL-1α, promoting neuroinflammation and parasite control.


Assuntos
Interleucina-1alfa/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Microglia/imunologia , Proteínas de Ligação a Fosfato/metabolismo , Toxoplasma/imunologia , Toxoplasmose Cerebral/imunologia , Animais , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/parasitologia , Encéfalo/patologia , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Humanos , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Microglia/metabolismo , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/imunologia , Toxoplasma/isolamento & purificação , Toxoplasmose Cerebral/sangue , Toxoplasmose Cerebral/parasitologia , Toxoplasmose Cerebral/patologia
7.
J Neuroimmunol ; 345: 577271, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32480239

RESUMO

Anti-Leucine Glioma Inactivated 1 (LGI-1) autoimmune encephalitis (AE) is a rare neuroinflammatory brain condition. Individuals afflicted with this condition can present with cognitive and psychological manifestations that can impact the individual's quality of life, day to day functioning, independence, return to work and interpersonal relationships. Our knowledge of the cognitive profiles and disease associated psychopathology is severely lacking. This review provides a comprehensive summary of the currently available literature, conceptualising our current understanding of the neuropsychological manifestations of anti LGI-1 AE and summarises methodological limitations of the current research to inform and improve future investigations. Key Terms: Autoimmune Diseases; Neuroimmunology; Autoimmune Encephalitis, Limbic Encephalitis; Anti-LGI1 Encephalitis, LGI1; Neuropsychology, Cognitive Assessment.


Assuntos
Autoanticorpos/imunologia , Encefalite/imunologia , Encefalite/psicologia , Doença de Hashimoto/imunologia , Doença de Hashimoto/psicologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Autoanticorpos/sangue , Estudos de Casos e Controles , Estudos de Coortes , Encefalite/sangue , Doença de Hashimoto/sangue , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/sangue
8.
Sci Rep ; 10(1): 7376, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355214

RESUMO

Radiation therapy has been shown to enhance the efficacy of various T cell-targeted immunotherapies that improve antigen-specific T cell expansion, T regulatory cell depletion, or effector T cell function. Additionally, radiation therapy has been proposed as a means to recruit T cells to the treatment site and modulate cancer cells as effector T cell targets. The significance of these features remains unclear. We set out to determine, in checkpoint inhibitor resistant models, which components of radiation are primarily responsible for overcoming this resistance. In order to model the vaccination effect of radiation, we used a Listeria monocytogenes based vaccine to generate a large population of tumor antigen specific T cells but found that the presence of cells with cytotoxic capacity was unable to replicate the efficacy of radiation with combination checkpoint blockade. Instead, we demonstrated that a major role of radiation was to increase the susceptibility of surviving cancer cells to CD8+ T cell-mediated control through enhanced MHC-I expression. We observed a novel mechanism of genetic induction of MHC-I in cancer cells through upregulation of the MHC-I transactivator NLRC5. These data support the critical role of local modulation of tumors by radiation to improve tumor control with combination immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Celular , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Membrana/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Transcrição Genética/imunologia , Regulação para Cima/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Antígenos de Histocompatibilidade Classe I/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/terapia , Radioterapia
9.
PLoS Pathog ; 16(5): e1008576, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32392230

RESUMO

Yersinia suppress neutrophil responses by using a type 3 secretion system (T3SS) to inject 6-7 Yersinia effector proteins (Yops) effectors into their cytoplasm. YopH is a tyrosine phosphatase that causes dephosphorylation of the adaptor protein SKAP2, among other targets in neutrophils. SKAP2 functions in reactive oxygen species (ROS) production, phagocytosis, and integrin-mediated migration by neutrophils. Here we identify essential neutrophil functions targeted by YopH, and investigate how the interaction between YopH and SKAP2 influence Yersinia pseudotuberculosis (Yptb) survival in tissues. The growth defect of a ΔyopH mutant was restored in mice defective in the NADPH oxidase complex, demonstrating that YopH is critical for protecting Yptb from ROS during infection. The growth of a ΔyopH mutant was partially restored in Skap2-deficient (Skap2KO) mice compared to wild-type (WT) mice, while induction of neutropenia further enhanced the growth of the ΔyopH mutant in both WT and Skap2KO mice. YopH inhibited both ROS production and degranulation triggered via integrin receptor, G-protein coupled receptor (GPCR), and Fcγ receptor (FcγR) stimulation. SKAP2 was required for integrin receptor and GPCR-mediated ROS production, but dispensable for degranulation under all conditions tested. YopH blocked SKAP2-independent FcγR-stimulated phosphorylation of the proximal signaling proteins Syk, SLP-76, and PLCγ2, and the more distal signaling protein ERK1/2, while only ERK1/2 phosphorylation was dependent on SKAP2 following integrin receptor activation. These findings reveal that YopH prevents activation of both SKAP2-dependent and -independent neutrophilic defenses, uncouple integrin- and GPCR-dependent ROS production from FcγR responses based on their SKAP2 dependency, and show that SKAP2 is not required for degranulation.


Assuntos
Proteínas da Membrana Bacteriana Externa/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Neutrófilos/imunologia , Proteínas Tirosina Fosfatases/imunologia , Transdução de Sinais/imunologia , Infecções por Yersinia pseudotuberculosis/imunologia , Yersinia pseudotuberculosis/imunologia , Animais , Peptídeos e Proteínas de Sinalização Intracelular/genética , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neutrófilos/patologia , Espécies Reativas de Oxigênio/imunologia , Transdução de Sinais/genética , Yersinia pseudotuberculosis/patogenicidade , Infecções por Yersinia pseudotuberculosis/genética , Infecções por Yersinia pseudotuberculosis/patologia
10.
Lakartidningen ; 1172020 04 08.
Artigo em Sueco | MEDLINE | ID: mdl-32293017

RESUMO

Anti-LGI-1 encephalitis is a type of autoimmune encephalopathy, where antibodies react against the cell surface protein leucine-rich glioma inactivated protein 1 (LGI-1). It presents with a subacute confusion, changes in behaviour, short-term memory deficits and seizures. A piloerectile semiology is common, which has been described as reflecting insular ictal activity. Patients may have temporal lobe abnormalities on brain MRI and EEG. More than half of the patients with limbic encephalitis associated with anti-LGI1 antibodies have hyponatremia. The diagnosis of anti-LGI-1 encephalitis can be made by the detection of antibodies against LGI-1 in serum and/or cerebrospinal fluid. Prompt diagnosis and treatment are important to avoid long-term disability. This case report describes a man with episodes of goose bumps and mild confusion caused by anti-LGI-1 encephalitis.


Assuntos
Encefalite , Doença de Hashimoto , Encefalite Límbica , Autoanticorpos , Encefalite/complicações , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Proteínas
11.
Cancer Res ; 80(12): 2537-2549, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32265222

RESUMO

The adaptor protein TNF receptor-associated factor 6 (TRAF6) is a key mediator in inflammation. However, the molecular mechanisms controlling its activity and stability in cancer progression remain unclear. Here we show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) inhibits the proinflammatory signaling pathway by targeting TRAF6 for degradation, thereby suppressing inflammatory signaling-mediated tumor growth and metastasis in advanced cervical cancer cells. DRAK1 bound directly to the TRAF domain of TRAF6, preventing its autoubiquitination by interfering with homo-oligomerization, eventually leading to autophagy-mediated degradation of TRAF6. Depletion of DRAK1 in cervical cancer cells resulted in markedly increased levels of TRAF6 protein, promoting activation of the IL1ß signaling-associated pathway and proinflammatory cytokine production. DRAK1 was specifically underexpressed in metastatic cervical cancers and inversely correlated with TRAF6 expression in mouse xenograft model tumor tissues and human cervical tumor tissues. Collectively, our findings highlight DRAK1 as a novel antagonist of inflammation targeting TRAF6 for degradation that limits inflammatory signaling-mediated progression of advanced cervical cancer. SIGNIFICANCE: Serine/threonine kinase DRAK1 serves a unique role as a novel negative regulator of the inflammatory signaling mediator TRAF6 in cervical cancer progression.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Autofagia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias do Colo do Útero/patologia , Animais , Linhagem Celular Tumoral , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Camundongos , Estadiamento de Neoplasias , Ligação Proteica/imunologia , Domínios Proteicos , Multimerização Proteica/imunologia , Estabilidade Proteica , Proteólise , Transdução de Sinais/imunologia , Análise Serial de Tecidos , Ubiquitinação/imunologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L953-L964, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32159971

RESUMO

The lungs and the immune and nervous systems functionally interact to respond to respiratory environmental exposures and infections. The lungs are innervated by vagal sensory neurons of the jugular and nodose ganglia, fused together in smaller mammals as the jugular-nodose complex (JNC). Whereas the JNC shares properties with the other sensory ganglia, the trigeminal (TG) and dorsal root ganglia (DRG), these sensory structures express differential sets of genes that reflect their unique functionalities. Here, we used RNA sequencing (RNA-seq) in mice to identify the differential transcriptomes of the three sensory ganglia types. Using a fluorescent retrograde tracer and fluorescence-activated cell sorting, we isolated a defined population of airway-innervating JNC neurons and determined their differential transcriptional map after pulmonary exposure to lipopolysaccharide (LPS), a major mediator of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after infection with gram-negative bacteria or inhalation of organic dust. JNC neurons activated an injury response program, leading to increased expression of gene products such as the G protein-coupled receptor Cckbr, inducing functional changes in neuronal sensitivity to peptides, and Gpr151, also rapidly induced upon neuropathic nerve injury in pain models. Unique JNC-specific transcripts, present at only minimal levels in TG, DRG, and other organs, were identified. These included TMC3, encoding for a putative mechanosensor, and urotensin 2B, a hypertensive peptide. These findings highlight the unique properties of the JNC and reveal that ALI/ARDS rapidly induces a nerve injury-related state, changing vagal excitability.


Assuntos
Gânglio Nodoso/efeitos dos fármacos , Pneumonia/genética , Receptor de Colecistocinina B/genética , Células Receptoras Sensoriais/efeitos dos fármacos , Transcriptoma , Traumatismos do Nervo Vago/genética , Animais , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/imunologia , Gânglios Espinais/patologia , Perfilação da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Gânglio Nodoso/imunologia , Gânglio Nodoso/patologia , Hormônios Peptídicos/genética , Hormônios Peptídicos/imunologia , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/patologia , Receptor de Colecistocinina B/imunologia , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/imunologia , Células Receptoras Sensoriais/imunologia , Células Receptoras Sensoriais/patologia , Análise de Sequência de RNA , Gânglio Trigeminal/efeitos dos fármacos , Gânglio Trigeminal/imunologia , Gânglio Trigeminal/patologia , Traumatismos do Nervo Vago/induzido quimicamente , Traumatismos do Nervo Vago/imunologia , Traumatismos do Nervo Vago/patologia
13.
Nat Immunol ; 21(2): 158-167, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31932809

RESUMO

STING (stimulator of interferon genes) is an important innate immune protein, but its homeostatic regulation at the resting state is unknown. Here, we identified TOLLIP as a stabilizer of STING through direct interaction to prevent its degradation. Tollip deficiency results in reduced STING protein in nonhematopoietic cells and tissues, and renders STING protein unstable in immune cells, leading to severely dampened STING signaling capacity. The competing degradation mechanism of resting-state STING requires IRE1α and lysosomes. TOLLIP mediates clearance of Huntington's disease-linked polyQ protein aggregates. Ectopically expressed polyQ proteins in vitro or endogenous polyQ proteins in Huntington's disease mouse striatum sequester TOLLIP away from STING, leading to reduced STING protein and dampened immune signaling. Tollip-/- also ameliorates STING-mediated autoimmune disease in Trex1-/- mice. Together, our findings reveal that resting-state STING protein level is strictly regulated by a constant tug-of-war between 'stabilizer' TOLLIP and 'degrader' IRE1α-lysosome that together maintain tissue immune homeostasis.


Assuntos
Homeostase/imunologia , Imunidade Inata/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Transdução de Sinais/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Exodesoxirribonucleases/deficiência , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Membrana/imunologia , Camundongos Knockout , Fosfoproteínas/deficiência
14.
Sci Immunol ; 5(43)2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953257

RESUMO

Cytokine release syndrome (CRS) counteracts the effectiveness of chimeric antigen receptor (CAR) T cell therapy in cancer patients, but the mechanism underlying CRS remains unclear. Here, we show that tumor cell pyroptosis triggers CRS during CAR T cell therapy. We find that CAR T cells rapidly activate caspase 3 in target cells through release of granzyme B. The latter cleaves gasdermin E (GSDME), a pore-forming protein highly expressed in B leukemic and other target cells, which results in extensive pyroptosis. Consequently, pyroptosis-released factors activate caspase 1 for GSDMD cleavage in macrophages, which results in the release of cytokines and subsequent CRS. Knocking out GSDME, depleting macrophages, or inhibiting caspase 1 eliminates CRS occurrence in mouse models. In patients, GSDME and lactate dehydrogenase levels are correlated with the severity of CRS. Notably, we find that the quantity of perforin/granzyme B used by CAR T cells rather than existing CD8+ T cells is critical for CAR T cells to induce target cell pyroptosis.


Assuntos
Síndrome da Liberação de Citocina/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Leucemia de Células B/imunologia , Proteínas de Ligação a Fosfato/imunologia , Piroptose/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Granzimas/imunologia , Humanos , Imunoterapia Adotiva , Leucemia de Células B/terapia , Macrófagos/imunologia , Camundongos , Perforina/imunologia
15.
Ann Neurol ; 87(3): 405-418, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900946

RESUMO

OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. METHODS: We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. RESULTS: Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. INTERPRETATION: Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418.


Assuntos
Anticorpos Monoclonais/farmacologia , Autoanticorpos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Neurônios/fisiologia , Proteínas ADAM/efeitos dos fármacos , Idoso , Animais , Anticorpos Monoclonais/líquido cefalorraquidiano , Autoanticorpos/líquido cefalorraquidiano , Região CA3 Hipocampal/fisiologia , Células Cultivadas , Encefalite/líquido cefalorraquidiano , Encefalite/imunologia , Feminino , Doença de Hashimoto/líquido cefalorraquidiano , Doença de Hashimoto/imunologia , Humanos , Isotipos de Imunoglobulinas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/efeitos dos fármacos , Ratos , Transmissão Sináptica/efeitos dos fármacos
16.
Int Immunopharmacol ; 78: 106072, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31835082

RESUMO

Although the novel resveratrol derivative RM has therapeutic potential for the treatment of inflammatory bowel disease, little is currently known regarding the manner whereby RM regulates excessive inflammatory responses. In this study, we initially investigated the molecular mechanisms underlying the anti-inflammatory effects induced by RM in Toll-like receptor (TLR)-activated macrophages. Upon stimulation with lipopolysaccharide, we found that RM-treated activated macrophages down-regulated the increase in pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß, and IL-12p70), nitric oxide (NO) production, and activating interleukin-1 receptor-associated kinase 1 (IRAK-1) phosphorylation, mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways. Interestingly, the TLR negative regulator Toll-interacting protein (Tollip) was selectively enhanced during RM stimulation in time- and dose-dependent manners. In response to knockdown of Tollip expression by RNA interference, RM-treated activated macrophages showed augmented expression of inflammatory mediators (pro-inflammatory cytokines, NO, inducible nitric oxidase, and cyclooxygenase-2, and surface molecules) and restored the expression of MAPK and NF-κB signals inhibited by RM treatment. Taken together, our findings indicate that RM has therapeutic potential for treating TLR-induced inflammatory diseases via the promotion of Tollip expression.


Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/efeitos dos fármacos , Resveratrol/farmacologia , Animais , Anti-Inflamatórios/efeitos da radiação , Anti-Inflamatórios/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Raios gama , Técnicas de Silenciamento de Genes , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Lipopolissacarídeos/imunologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Cultura Primária de Células , Células RAW 264.7 , Resveratrol/análogos & derivados , Resveratrol/efeitos da radiação , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Receptores Toll-Like/metabolismo , Regulação para Cima
17.
EMBO J ; 39(2): e103397, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31793683

RESUMO

Programmed cell death is a key mechanism involved in several biological processes ranging from development and homeostasis to immunity, where it promotes the removal of stressed, damaged, malignant or infected cells. Abnormalities in the pathways leading to initiation of cell death or removal of dead cells are consequently associated with a range of human diseases including infections, autoinflammatory disease, neurodegenerative disease and cancer. Apoptosis, pyroptosis and NETosis are three well-studied modes of cell death that were traditionally believed to be independent of one another, but emerging evidence indicates that there is extensive cross-talk between them, and that all three pathways can converge onto the activation of the same cell death effector-the pore-forming protein Gasdermin D (GSDMD). In this review, we highlight recent advances in gasdermin research, with a particular focus on the role of gasdermins in pyroptosis, NETosis and apoptosis, as well as cell type-specific consequences of gasdermin activation. In addition, we discuss controversies surrounding a related gasdermin family protein, Gasdermin E (GSDME), in mediating pyroptosis and secondary necrosis following apoptosis, chemotherapy and inflammasome activation.


Assuntos
Apoptose , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Necrose , Neoplasias/patologia , Neutrófilos/patologia , Proteínas de Ligação a Fosfato/metabolismo , Piroptose , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Neoplasias/metabolismo , Neutrófilos/metabolismo , Proteínas de Ligação a Fosfato/imunologia
18.
Ann Neurol ; 87(2): 313-323, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31782181

RESUMO

OBJECTIVE: Drug-resistant seizures are common in patients with leucine-rich, glioma-inactivated 1 (LGI1)-IgG associated and contactin-associated protein-like 2 (CASPR2)-IgG associated encephalitis. We performed the first randomized double-blind placebo-controlled trial to evaluate efficacy of intravenous immunoglobulin (IVIG) in reducing seizure frequency. METHODS: Our enrollment goal was 30 LGI1/CASPR2-IgG-seropositive adult patients with ≥2 seizures per week. Patients were randomized to receive IVIG (0.5g/kg day 1, 1g/kg day 2, 0.6g/kg weeks 3 and 5) or volume-matched intravenous normal saline. Following the blinded phase, the nonresponders in the placebo group received IVIG. The primary clinical outcome was 50% reduction in seizure frequency from baseline to 5 weeks. RESULTS: After enrollment of 17 patients (LGI1-IgG, 14; CASPR2-IgG, 3) over 34 months, the study was terminated due to slow enrollment. Six of 8 patients in the IVIG group were responders, compared to 2 of 9 in the placebo group (p = 0.044, odds ratio = 10.5, 95% confidence interval = 1.1-98.9). For the LGI1-IgG seropositive subgroup, 6 of 8 patients in the IVIG group were responders, compared to zero of 6 in the placebo group. Two LGI1-IgG-seropositive patients receiving IVIG, but none receiving placebo, were seizure-free at the end of the blinded phase. Four of the 6 patients entering the open-label IVIG arm reported ≥50% reduction in seizure frequency. There were no correlations with LGI1/CASPR2-IgG1-4 subclasses. INTERPRETATION: Superiority of IVIG to placebo reached statistical significance for the primary endpoint for all patients and the subset with LGI1-IgG. These results have to be interpreted with the caveat that the study did not reach its originally selected sample size. ANN NEUROL 2020;87:313-323.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Epilepsia/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Idoso , Autoanticorpos/sangue , Método Duplo-Cego , Epilepsia/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Masculino , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/sangue , Resultado do Tratamento
19.
Fish Shellfish Immunol ; 98: 34-44, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883472

RESUMO

Ctenopharyngodon idella growth arrest and DNA damage-inducible 45 ab (CiGadd45ab) is a subtype of the Gadd45a gene of the Gadd45 family in grass carp. There is increasing evidence that microRNAs (miRNAs) are involved in the regulation of inflammatory and apoptotic responses. However, little is known about the regulatory effects of miRNAs on CiGadd45ab expression. In the present study, CiGadd45ab was identified as a target gene of miR-23a-3p and miR-23a-5p, based on miRNA expression profiling and a dual-luciferase reporter assay. In addition, miR-23a-3p and miR-23a-5p were both confirmed to be involved in the inflammatory response following infection with Aeromonas hydrophila by targeting CiGadd45ab. Transfection with miR-23a-3p and miR-23a-5p mimics and inhibitor altered proinflammatory gene expression and apoptosis rate, thereby suggesting that miRNAs regulate immune response and anti-apoptosis by targeting CiGadd45ab in grass carp. Our results provide a theoretical basis for exploring the molecular mechanisms by which miR-23a-3p and miR-23a-5p target CiGadd45ab to regulate inflammation and apoptosis against bacterial infection in grass carp.


Assuntos
Apoptose/imunologia , Carpas/genética , Carpas/imunologia , Doenças dos Peixes/imunologia , Inflamação/veterinária , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Aeromonas hydrophila/fisiologia , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , MicroRNAs/imunologia
20.
Clin Immunol ; 212: 108249, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31445170

RESUMO

Genetic aberrations in the toll-like receptor (TLR)3 pathway are associated with increased susceptibility to herpes simplex virus (HSV) infections. Leucine-rich repeat and PYD-containing protein (NLRP)12 is a component of the inflammasome apparatus, which is critical to an immediate innate inflammatory response. Aberrations in NLRP12 have been shown to mediate auto-inflammation. In this study, we present a 44-year old patient with severe HSV esophagitis and Crohn's disease. An immune and genetic investigation confirmed two coinciding genetic mutations in TLR3 and NLRP12. Our findings support conducting laboratory workup that targets TLR3 pathway in the immunocompetent host developing recurrent HSV infections.


Assuntos
Doença de Crohn/genética , Esofagite/genética , Herpes Simples/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Receptor 3 Toll-Like/genética , Aciclovir/uso terapêutico , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Doença de Crohn/imunologia , Esofagite/imunologia , Esofagite/virologia , Feminino , Fármacos Gastrointestinais/uso terapêutico , Herpes Simples/tratamento farmacológico , Herpes Simples/imunologia , Herpes Simples/prevenção & controle , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Mutação , Transdução de Sinais , Receptor 3 Toll-Like/imunologia , Valganciclovir/uso terapêutico , Sequenciamento Completo do Genoma
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