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1.
Pediatr Rheumatol Online J ; 17(1): 22, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088470

RESUMO

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease in Canada and is characterized by a clinical syndrome of episodic inflammatory symptoms. Traditionally, the disease is defined by autosomal recessive inheritance of MEFV gene variants, yet FMF also not uncommonly manifests in individuals with only one identified disease-associated allele. Increasing availability and affordability of gene sequencing has led to the identification of multiple MEFV variants; however, they are often of unknown clinical significance. Variants in other genes affecting overlapping or distinct inflammatory signaling pathways - together with gene-environment interactions including epigenetic modulation - likely underlie the significant genetic and phenotypic heterogeneity seen among patients with this disease. We review recent evidence of the expanding spectrum of FMF genotype and phenotype and suggest that current drug funding schemes restricting biologic agents to patients with homozygous mutations have not kept pace with our biological understanding of the disease.


Assuntos
Febre Familiar do Mediterrâneo/genética , Terapia Biológica/métodos , Criança , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/terapia , Genótipo , Humanos , Mutação/genética , Pirina/genética , Pirina/metabolismo
2.
Microbiol Spectr ; 7(2)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30848231

RESUMO

Inflammasomes are multiprotein signaling complexes that are assembled by cytosolic sensors upon the detection of infectious or noxious stimuli. These complexes activate inflammatory caspases to induce host cell death and cytokine secretion and are an essential part of antimicrobial host defense. In this review, I discuss how intracellular bacteria are detected by inflammasomes, how the specific sensing mechanism of each inflammasome receptor restricts the ability of bacteria to evade immune recognition, and how host cell death is used to control bacterial replication in vivo.


Assuntos
Bactérias/isolamento & purificação , Citosol/microbiologia , Inflamassomos/metabolismo , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Anti-Infecciosos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Bactérias/patogenicidade , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Morte Celular , Citocinas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Evasão da Resposta Imune , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína Inibidora de Apoptose Neuronal/metabolismo , Pirina/metabolismo , Piroptose/efeitos dos fármacos
3.
Am J Clin Dermatol ; 20(3): 325-333, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30632096

RESUMO

Neutrophilic dermatoses (ND) are a group of conditions characterized by an aseptic accumulation of polymorphonuclear leukocytes in the skin. Occurrence of ND in association with myeloid malignancies, mainly myelodysplastic syndrome and myelogenous acute leukemia, is not rare and is often associated with a poor prognosis. Recent findings have improved understanding of the pathophysiology of myeloid malignancy-associated ND. We review the clinical spectrum of myeloid malignancy-associated ND with an emphasis on recently identified mechanisms. Myeloid leukemia cells retain the potential for terminal differentiation into polymorphonuclear leukocytes in the skin. Many studies suggest a clonal link between myeloid malignancies and ND. Activation of autoinflammatory pathways (NOD-like receptor family pyrin domain-containing-3, Familial Mediterranean Fever Gene) in the clonal cells of myeloid disorders may also be involved in this setting.


Assuntos
Leucemia Mieloide/complicações , Síndromes Mielodisplásicas/complicações , Neutrófilos/imunologia , Transdução de Sinais/imunologia , Dermatopatias/imunologia , Diferenciação Celular/imunologia , Diagnóstico Diferencial , Humanos , Leucemia Mieloide/imunologia , Síndromes Mielodisplásicas/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neutrófilos/metabolismo , Pirina/metabolismo , Pele/citologia , Pele/imunologia , Pele/patologia , Dermatopatias/diagnóstico , Dermatopatias/patologia
4.
Infect Immun ; 87(3)2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30602502

RESUMO

Pathogenic Yersinia species deliver Yop effector proteins through a type III secretion system into host cells. Among these effectors, YopE and YopT are Rho-modifying toxins, which function to modulate host cell physiology and evade immune responses. YopE is a GTPase-activating protein (GAP) while YopT is a protease, and they inhibit RhoA by different modes of action. Modifications to RhoA are sensed by pyrin, which, once activated, assembles a caspase-1 inflammasome, which generates cytokines such as interleukin-1ß (IL-1ß) and cell death by pyroptosis. In Yersinia-infected macrophages, YopE or YopT triggers inflammasome assembly only in the absence of another effector, YopM, which counteracts pyrin by keeping it inactive. The glucosyltransferase TcdB from Clostridium difficile, a well-studied RhoA-inactivating toxin, triggers activation of murine pyrin by dephosphorylation of Ser205 and Ser241. To determine if YopE or YopT triggers pyrin dephosphorylation, we infected lipopolysaccharide (LPS)-primed murine macrophages with ΔyopM Yersinia pseudotuberculosis strains expressing wild-type (wt) or YopE mutant variants or YopT. By immunoblotting pyrin after infection, we observed that wt YopE triggered dephosphorylation of Ser205 and inflammasome activation. Pyrin dephosphorylation was reduced if a YopE variant had a defect in stability or RhoA specificity but not membrane localization. We also observed that wt YopT triggered pyrin dephosphorylation but more slowly than YopE, suggesting that YopE is dominant in this process. Our findings provide evidence that RhoA-modifying toxins trigger activation of pyrin by a conserved dephosphorylation mechanism. In addition, by characterization of YopE and YopT, we show that different features of effectors, such as RhoA specificity, affect the efficiency of pyrin dephosphorylation.


Assuntos
Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Bactérias/imunologia , Cisteína Endopeptidases/imunologia , Inflamassomos/metabolismo , Macrófagos/metabolismo , Pirina/metabolismo , Yersinia/metabolismo , Proteínas da Membrana Bacteriana Externa/metabolismo , Proteínas de Bactérias/metabolismo , Cisteína Endopeptidases/metabolismo , Macrófagos/imunologia , Fosforilação
5.
Intern Med ; 58(7): 1017-1022, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30568124

RESUMO

We herein report a case of a 75-year-old woman who presented with a low-grade fever, repeated cold-induced urticaria, and painful leg edemas with neutrocytosis. Because her mother also had cold-induced urticaria and her skin lesions histologically showed neutrophilic dermatitis, we suspected that she had familial cold autoinflammatory syndrome, a subtype of cryopyrin-associated periodic syndromes. Sequencing of the NLRP3 and MEFV genes revealed that she carried both the p.A439V missense mutation and p.E148Q homozygous mutation, which is commonly detected in familial Mediterranean fever patients. The administration of colchicine reduced the frequency and severity of her skin rash and leg edema.


Assuntos
Síndromes Periódicas Associadas à Criopirina/diagnóstico , DNA/genética , Mutação , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pirina/genética , Idoso , Biópsia , Síndromes Periódicas Associadas à Criopirina/genética , Análise Mutacional de DNA , Febre Familiar do Mediterrâneo/genética , Feminino , Homozigoto , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pirina/metabolismo , Doenças Raras
6.
Clin Exp Rheumatol ; 36(6 Suppl 115): 116-124, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30582517

RESUMO

Familial Mediterranean fever (FMF), the most common of the systemic autoinflammatory disorders, is caused by mutations in the MEFV (Mediterranean Fever) gene, which encodes the protein pyrin. Neutrophils, one of the major components during inflammation, are the main cell type that expresses pyrin. In response to an inflammatory stimulus, neutrophils migration to their main active site. To date, several pyrin-interacting proteins have been demonstrated to co-localise with the cytoskeletal protein actin, which is important in the process of neutrophil migration and raises the question of whether pyrin plays a role in the actin cytoskeletal network during inflammatory cell migration. In this study, we examined the possible role of pyrin during inflammatory cell migration in neutrophils. We generated a cell migration assay with neutrophils and primary neutrophils from patients. We also knocked down pyrin expression using siRNA and then performed cell migration assay. We showed co-localisation of pyrin and F-actin at the leading edge during inflammatory cell migration. In pyrin knocked down cells, we identified a significant decrease in neutrophil migration. In addition, we demonstrated a dramatic increase in migration in the neutrophils of FMF patients compared with a healthy control group. These data together provide new insight into the cellular function of pyrin and demonstrate an important link between pyrin and polymerising actin in the process of inflammatory cell migration.


Assuntos
Quimiotaxia de Leucócito , Febre Familiar do Mediterrâneo/genética , Mutação , Neutrófilos/metabolismo , Pirina/genética , Pirina/metabolismo , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/imunologia , Febre Familiar do Mediterrâneo/metabolismo , Feminino , Predisposição Genética para Doença , Células HL-60 , Humanos , Masculino , Neutrófilos/imunologia , Fenótipo , Transdução de Sinais
7.
J Exp Med ; 215(6): 1519-1529, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29793924

RESUMO

Pyroptosis is an inflammasome-induced lytic cell death mode, the physiological role of which in chronic inflammatory diseases is unknown. Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting an estimated 150,000 patients. The disease is caused by missense mutations in Mefv that activate the Pyrin inflammasome, but the pathophysiologic mechanisms driving autoinflammation in FMF are incompletely understood. Here, we show that Clostridium difficile infection of FMF knock-in macrophages that express a chimeric FMF-associated MefvV726A Pyrin elicited pyroptosis and gasdermin D (GSDMD)-mediated interleukin (IL)-1ß secretion. Importantly, in vivo GSDMD deletion abolished spontaneous autoinflammatory disease. GSDMD-deficient FMF knock-in mice were fully protected from the runted growth, anemia, systemic inflammatory cytokine production, neutrophilia, and tissue damage that characterize this autoinflammatory disease model. Overall, this work identifies pyroptosis as a critical mechanism of IL-1ß-dependent autoinflammation in FMF and highlights GSDMD inhibition as a potential antiinflammatory strategy in inflammasome-driven diseases.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Febre Familiar do Mediterrâneo/metabolismo , Febre Familiar do Mediterrâneo/patologia , Inflamação/metabolismo , Inflamação/patologia , Animais , Clostridium difficile/fisiologia , Citocinas/biossíntese , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Neutrófilos/patologia , Pirina/metabolismo , Pirina/farmacologia , Piroptose , Baço/patologia , Síndrome de Emaciação/patologia
8.
Curr Opin Immunol ; 50: 32-38, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29128729

RESUMO

The inflammasome is a complex of proteins that through the activity of caspase-1 and the downstream substrates gasdermin D, IL-1ß, and IL-18 execute an inflammatory form of cell death termed pyroptosis. Activation of this complex often involves the adaptor protein ASC and upstream sensors including NLRP1, NLRP3, NLRC4, AIM2, and pyrin, which are activated by different stimuli including infectious agents and changes in cell homeostasis. Here we discuss new regulatory mechanisms that have been identified for the canonical inflammasomes, the most recently identified NLRP9b inflammasome, and the new gasdermin family of proteins that mediate pyroptosis and other forms of regulated cell death.


Assuntos
Inflamassomos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína Inibidora de Apoptose Neuronal/metabolismo , Pirina/metabolismo
9.
J Leukoc Biol ; 103(2): 233-257, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28855232

RESUMO

The inflammasome is a macromolecular protein complex that mediates proteolytic cleavage of pro-IL-1ß and -IL-18 and induces cell death in the form of pyroptosis. Certain nucleotide-binding oligomerization domain-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), or tripartite motif (TRIM) family receptors trigger the assembly of an inflammasome in response to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Recent studies have revealed a multitude of host components and signals that are essential for controlling canonical and noncanonical inflammasome activation and pyroptosis. These include pore-forming gasdermin proteins, the never in mitosis A-related kinase 7 (NEK7), IFN-inducible proteins (IFIs), reactive oxygen species (ROS), autophagy, potassium efflux, mitochondrial perturbations, and microbial metabolites. Here, we provide a comprehensive overview of the molecular and signaling mechanisms that provide stringent regulation over the activation and effector functions of the inflammasome.


Assuntos
Inflamassomos/metabolismo , Inflamação/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Neoplasias/metabolismo , Pirina/metabolismo
10.
Int Ophthalmol ; 38(1): 183-190, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28108907

RESUMO

OBJECTIVE: The purpose of the present study was to evaluate the thickness of the peripapillary retinal nerve fiber layer (RNFL) and retinal ganglion cell-inner plexiform layer (GCIPL) in adult-onset familial Mediterranean fever (FMF). METHODS: Forty two adult-onset FMF patients and forty two healthy controls were included in the present study. Detailed ocular examination was performed, and then the thickness of the peripapillary RNFL and GCIPL was measured by Spectral domain optical coherence tomography. The patients were divided into two groups according to their disease severity score, M694V gene mutation, colchicine dosage used per day, colchicine usage time period and number of FMF attacks per year. RESULTS: There were no statistically significant differences in peripapillary RNFL and retinal GCIPL thickness in patients with adult-onset FMF and controls. CONCLUSION: According to our study, it looks like that neither adult-onset FMF nor colchicine has any effect on the RNFL and GCIPL thicknesses. Further studies with a large sample size are needed.


Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Fibras Nervosas/patologia , Disco Óptico/patologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Adulto , Cromossomos Humanos Par 16/genética , Colchicina/administração & dosagem , DNA , Análise Mutacional de DNA , Relação Dose-Resposta a Droga , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Feminino , Humanos , Masculino , Mutação , Pirina/genética , Pirina/metabolismo , Índice de Gravidade de Doença , Moduladores de Tubulina/administração & dosagem
11.
Eur Cytokine Netw ; 29(4): 127-135, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698144

RESUMO

Familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disorder. The caspase-1-dependent cytokine, IL-1ß, plays an important role in FMF pathogenesis, and RAC1 protein has been recently involved in IL-1ß secretion. This study aims to investigate RAC1 expression and role in IL-1ß and caspase-1 production and oxidative stress generation in FMF. The study included 25 FMF patients (nine during attack and remission, and 16 during remission only), and 25 controls. RAC1 expression levels were analyzed by real-time PCR. Ex vivo production of caspase-1, IL-1ß, IL-6 and markers of oxidative stress (malondialdehyde, catalase, and glutathione system) were evaluated respectively in supernatants of patients' and controls' PBMC and PMN cultures, in the presence and absence of RAC1 inhibitor. RAC1 gene expression and IL-1ß levels were increased in patients in crises compared to those in remission or controls. RAC1 expression levels were correlated with MEFV genotypes, patients carrying the M694V/M694V genotype having a two-fold increase in the expression levels compared to those carrying other genotypes. Caspase-1 levels were higher in LPS-induced PBMC of patients in remission than controls. Spontaneous and LPS-induced IL-1ß production were comparable in patients in remission and controls, whereas LPS-induced IL-6 production was enhanced in patients, compared to controls. RAC1 inhibition resulted in a decrease in caspase-1 and IL-1ß, but not IL-6, levels. Malondialdehyde levels produced by LPS-stimulated PMNs were increased in patients in remission compared to those in controls, but decreased following RAC1 inhibition. Catalase and GSH activities were reduced in unstimulated PMN culture supernatants of patients in remission compared to controls and were increased in the presence of RAC1 inhibitor. These results show the involvement of RAC1 in the inflammatory process of FMF by enhancing IL-1ß production, through caspase-1 activation, and generating oxidative stress, even during asymptomatic periods.


Assuntos
Febre Familiar do Mediterrâneo/metabolismo , Interleucina-1beta/metabolismo , Estresse Oxidativo/fisiologia , Proteínas rac1 de Ligação ao GTP/metabolismo , Adulto , Biomarcadores/metabolismo , Caspase 1/metabolismo , Feminino , Genótipo , Humanos , Inflamação/metabolismo , Interleucina-6/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pirina/metabolismo
12.
PLoS One ; 13(12): e0209931, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30596757

RESUMO

Although the study of pathogen sensing by host defense systems continues to uncover a role for inflammasome components specific to particular pathogens, gaps remain in our knowledge. After internalization, Francisella escapes from the phagosome in mononuclear cells and is thought to be detected by intracellular pathogen-response-receptors pyrin and Aim2 in human and murine models, respectively. However, it remains controversial as to the role of pyrin in detecting Francisella. Our current work aims to study the contribution of inflammasome sensor, Pyrin in regulating microparticulate caspase-1/GSDM-D activation by Francisella. Our findings suggest that NLRP3 is central to the activation/release of active caspase-1/GSDM-D encapsulated in microparticles (MP) by Francisella. We also provide evidence that this regulation is independent of pyrin, implicated in sensing cytosolic Francisella in NLRP3-/- conditions where endogenous Pyrin is present. Absence of NLRP3 completely abrogated Francisella mediated MP caspase-1/GSDM-D activation and release both before and after internalization of the pathogen. However, deletion of pyrin not only enhanced both LPS and Francisella mediated MP active caspase-1/GSDM-D release, but pyrin overexpression resulted in a reduction of inflammasome activation and release; suggesting an inhibitory role of pyrin in LPS and Francisella mediated MP responses. This NLRP3 dependence and inhibitory effect of pyrin correlated with cytokine release as well. These observations also correlated with MPs ability to induce cell death; as LPS and Francisella-induced MPs from pyrin-deficient cells were more potent than wild-type monocytes whereas, NLRP3-/- MPs failed to induce cell death. Taken together, we report that NLPR3 not only mediates Francisella induced cytokine responses, but is also critical for cytokine-independent microparticle-induced inflammasome activation and endothelial cell injury independent of pyrin.


Assuntos
Caspase 1/metabolismo , Francisella/química , Inflamassomos/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Neoplasias/metabolismo , Pirina/metabolismo , Animais , Caspase 1/genética , Humanos , Inflamassomos/genética , Lipopolissacarídeos/química , Camundongos , Monócitos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Neoplasias/genética , Pirina/genética , Células THP-1
13.
Gastroenterology ; 154(4): 948-964.e8, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29203393

RESUMO

BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) increase risk for colorectal cancer. Mutations in the Mediterranean fever gene (MEFV or pyrin) are associated with hereditary autoinflammatory disease and severe IBD. Expression of MEFV, a sensor protein that the initiates assembly of the inflammasome complex, is increased in colon biopsies from patients with IBD. We investigated the role of pyrin in intestinal homeostasis in mice. METHODS: Mefv-/- mice and C57/BL6 mice (controls) were given azoxymethane followed by multiple rounds of dextran sodium sulfate (DSS) to induce colitis and tumorigenesis. In some experiments, Mefv-/- mice were given injections of recombinant interleukin 18 (rIL18) or saline (control) during DSS administration. Colon tissues were collected at different time points during colitis development and analyzed by histology, immunohistochemistry, immunoblots, or ELISAs (to measure cytokines). Spleen and mesenteric lymph node were collected, processed, and analyzed by flow cytometry. Colon epithelial permeability was measured in mice with colitis by gavage of fluorescent dextran and quantification of serum levels. RESULTS: MEFV was expressed in colons of control mice and expression increased during chronic and acute inflammation; high levels were detected in colon tumor and adjacent non-tumor tissues. Mefv-/- mice developed more severe colitis than control mice, with a greater extent of epithelial hyperplasia and a larger tumor burden. Levels of inflammatory cytokines (IL6) and chemokines were significantly higher in colons of Mefv-/- mice than control mice following colitis induction, whereas the level IL18, which depends on the inflammasome for maturation and release, was significantly lower in colons of Mefv-/- mice. Mefv-/- mice had increased epithelial permeability following administration of DSS than control mice, and loss of the tight junction proteins occludin and claudin-2 from intercellular junctions. STAT3 was activated (phosphorylated) in inflamed colon tissues from Mefv-/-, which also had increased expression of stem cell markers (OLFM4, BMI1, and MSI1) compared with colons from control mice. Administration of rIL18 to Mefv-/- mice reduced epithelial permeability, intestinal inflammation, the severity of colitis, and colon tumorigenesis. CONCLUSIONS: In studies with DSS-induced colitis, we found that pyrin (MEFV) is required for inflammasome activation and IL18 maturation, which promote intestinal barrier integrity and prevent colon inflammation and tumorigenesis. Strategies to increase activity of MEFV or IL18 might be developed for the treatment of IBD and prevention of colitis-associated tumorigenesis.


Assuntos
Transformação Celular Neoplásica/metabolismo , Colite/metabolismo , Colo/metabolismo , Neoplasias do Colo/metabolismo , Inflamassomos/metabolismo , Pirina/metabolismo , Junções Íntimas/metabolismo , Animais , Azoximetano , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Colite/imunologia , Colite/patologia , Colite/prevenção & controle , Colo/imunologia , Colo/patologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias do Colo/prevenção & controle , Sulfato de Dextrana , Modelos Animais de Doenças , Predisposição Genética para Doença , Inflamassomos/imunologia , Interleucina-18/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Permeabilidade , Fenótipo , Fosforilação , Pirina/deficiência , Pirina/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Junções Íntimas/imunologia , Junções Íntimas/patologia , Fatores de Tempo , Carga Tumoral , Microambiente Tumoral
14.
Immunol Rev ; 281(1): 115-123, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29247997

RESUMO

15 years ago, the fundamental biology of an inflammatory signaling complex eventually dubbed "the inflammasome" began to unravel in chronologic parallel with the discovery that many inflammatory diseases were associated with its hyperactivity. Though the genetic origins of Familial Mediterranean Fever (FMF, caused my mutations in MEFV) were discovered first, it would take nearly two decades before the mechanistic connections to a PYRIN inflammasome were made. In the interim, the intensive study of the NLRP3 inflammasome, and the diseases associated with its hyperactivation, have largely dictated the paradigm of inflammasome composition and function. Despite impressive gains, focusing on NLRP3 left gaps in our understanding of inflammasome biology. Foremost among these gaps were how inflammasomes become activated and the connections between inflammasome structure and function. Fortunately, work in another inflammasome inducer, NLRC4, grew to fill those gaps. The current understanding of the NLRC4 inflammasome is perhaps the most comprehensive illustration of the inflammasome paradigm: trigger (e.g. cytosolic flagellin), sensor (NAIP), nucleator (NLRC4), adaptor (ASC), and effector (CASP1). Detailed work has also identified observations that challenge this paradigm. Simultaneously, the features unique to each inflammasome offer a lesson in contrast, providing perspectives on inflammasome activation, regulation, and function. In this review, we endeavor to highlight recent breakthroughs related to NLRC4 inflammasome structure and activation, important in vivo work in infection and systemic inflammation, and the characterization of a spectrum of human NLRC4-associated autoinflammatory diseases.


Assuntos
Doenças Autoimunes/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Febre Familiar do Mediterrâneo/genética , Inflamassomos/metabolismo , Inflamação/metabolismo , Pirina/metabolismo , Animais , Doenças Autoimunes/genética , Humanos , Pirina/genética , Transdução de Sinais
15.
Adv Exp Med Biol ; 1024: 1-35, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28921463

RESUMO

The families of innate immune receptors are the frontline responders to danger. These superheroes of the host immune systems populate innate immune cells, surveying the extracellular environment and the intracellular endolysosomal compartments and cytosol for exogenous and endogenous danger signals. As a collective the innate immune receptors recognise a wide array of stimuli, and in response they initiate specific signalling pathways leading to activation of transcriptional or proteolytic pathways and the production of inflammatory molecules to destroy foreign pathogens and/or resolve tissue injury. In this review, I will give an overview of the innate immune system and the activation and effector functions of the families of receptors it comprises. Current key concepts will be described throughout, including innate immune memory, formation of innate immune receptor signalosomes, inflammasome formation and pyroptosis, methods of extrinsic cell communication and examples of receptor cooperation. Finally, several open questions and future directions in the field of innate immunity will be presented and discussed.


Assuntos
Imunidade Inata/fisiologia , Proteínas NLR/metabolismo , Pirina/metabolismo , Receptores Toll-Like/metabolismo , Vertebrados/imunologia , Animais , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Memória Imunológica/fisiologia , Inflamassomos/imunologia , Inflamação/imunologia , Inflamação/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Proteínas NLR/genética , Pirina/genética , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/imunologia , Receptores Toll-Like/genética
16.
Curr Opin Rheumatol ; 29(5): 506-515, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28604422

RESUMO

PURPOSE OF REVIEW: Practitioners dazed by the evolving concept of autoinflammation are in good company. Despite the clinical challenges autoinflammatory patients present, their study has been fundamental to our understanding of basic human inflammation. This review will focus on the ways in which recent discoveries in genetically mediated autoinflammation broaden and refine the concept. RECENT FINDINGS: Major developments in pyrin inflammasome biology, defective ubiquitination, and the hyperferritinemic syndromes will be highlighted. SUMMARY: We offer a brief discussion of discordance, convergence, genotype, and phenotype in autoinflammation. Additionally, we introduce the concepts of mutation dose effect and hybrid nomenclature. Overall, we hope to provide an update on developments in the field of autoinflammation, some conceptual tools to help navigate the rising tide of discovery, and some encouragement that keeping up with developments in autoinflammation is both exciting and necessary.


Assuntos
Autoimunidade/genética , Doenças Hereditárias Autoinflamatórias/genética , Inflamassomos/genética , Inflamação/genética , Mutação/genética , Pirina/genética , Doenças Hereditárias Autoinflamatórias/metabolismo , Humanos , Fenótipo , Pirina/metabolismo
17.
Cell Mol Immunol ; 14(4): 349-359, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26435068

RESUMO

Carbon monoxide (CO) can act as an anti-inflammatory effector in mouse models of lung injury and disease, through the downregulation of pro-inflammatory cytokines production, though the underlying mechanisms remain unclear. The nucleotide-binding oligomerization domain-, leucine-rich region-, and pyrin domain-containing-3 (NLRP3) inflammasome is a protein complex that regulates the maturation and secretion of pro-inflammatory cytokines, including interleukin-1ß (IL-1ß). In this report, we show that the CO-releasing molecule (CORM-2) can stimulate the expression of pyrin, a negative regulator of the NLRP3 inflammasome. CORM-2 increased the transcription of pyrin in the human leukemic cell line (THP-1) in the absence and presence of lipopolysaccharide (LPS). In THP-1 cells, CORM-2 treatment dose-dependently reduced the activation of caspase-1 and the secretion of IL-1ß, and increased the levels of IL-10, in response to LPS and adenosine 5'-triphosphate (ATP), an NLRP3 inflammasome activation model. Genetic interference of IL-10 by small interfering RNA (siRNA) reduced the effectiveness of CORM-2 in inhibiting IL-1ß production and in inducing pyrin expression. Genetic interference of pyrin by siRNA increased IL-1ß production in response to LPS and ATP, and reversed CORM-2-dependent inhibition of caspase-1 activation. CO inhalation (250 ppm) in vivo increased the expression of pyrin and IL-10 in lung and spleen, and decreased the levels of IL-1ß induced by LPS. Consistent with the induction of pyrin and IL-10, and the downregulation of lung IL-1ß production, CO provided protection in a model of acute lung injury induced by intranasal LPS administration. These results provide a novel mechanism underlying the anti-inflammatory effects of CO, involving the IL-10-dependent upregulation of pyrin expression.


Assuntos
Monóxido de Carbono/farmacologia , Interleucina-1beta/metabolismo , Pulmão/metabolismo , Pirina/metabolismo , Animais , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Humanos , Interleucina-10/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Pirina/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo
18.
Proc Natl Acad Sci U S A ; 113(50): 14384-14389, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27911804

RESUMO

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is caused by mutations in the inflammasome adaptor Pyrin, but how FMF mutations alter signaling in FMF patients is unknown. Herein, we establish Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wild-type and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1ß and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other autoinflammatory diseases. We further demonstrate that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and that FMF mutations enable microtubule-independent assembly of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) micrometer-sized perinuclear structures (specks). The discovery that Pyrin mutations remove the obligatory requirement for microtubules in inflammasome activation provides a conceptual framework for understanding FMF and enables immunological screening of FMF mutations.


Assuntos
Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/metabolismo , Inflamassomos/metabolismo , Mutação , Pirina/genética , Pirina/metabolismo , Animais , Toxinas Bacterianas/toxicidade , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Infecções por Clostridium/imunologia , Infecções por Clostridium/metabolismo , Enterotoxinas/toxicidade , Febre Familiar do Mediterrâneo/imunologia , Células HEK293 , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/imunologia , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microtúbulos/efeitos dos fármacos , Microtúbulos/imunologia , Microtúbulos/metabolismo , Pirina/imunologia , Tubulina (Proteína)/metabolismo
19.
Cell Host Microbe ; 20(3): 296-306, 2016 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-27569559

RESUMO

Pathogenic Yersinia, including Y. pestis, the agent of plague in humans, and Y. pseudotuberculosis, the related enteric pathogen, deliver virulence effectors into host cells via a prototypical type III secretion system to promote pathogenesis. These effectors, termed Yersinia outer proteins (Yops), modulate multiple host signaling responses. Studies in Y. pestis and Y. pseudotuberculosis have shown that YopM suppresses infection-induced inflammasome activation; however, the underlying molecular mechanism is largely unknown. Here we show that YopM specifically restricts the pyrin inflammasome, which is triggered by the RhoA-inactivating enzymatic activities of YopE and YopT, in Y. pseudotuberculosis-infected macrophages. The attenuation of a yopM mutant is fully reversed in pyrin knockout mice, demonstrating that YopM inhibits pyrin to promote virulence. Mechanistically, YopM recruits and activates the host kinases PRK1 and PRK2 to negatively regulate pyrin by phosphorylation. These results show how a virulence factor can hijack host kinases to inhibit effector-triggered pyrin inflammasome activation.


Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , Proteína Quinase C/metabolismo , Pirina/antagonistas & inibidores , Yersinia pseudotuberculosis/patogenicidade , Animais , Proteínas de Bactérias/metabolismo , Cisteína Endopeptidases/metabolismo , Inflamassomos/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Processamento de Proteína Pós-Traducional , Pirina/metabolismo , Análise de Sobrevida , Virulência , Fatores de Virulência/metabolismo , Yersinia pseudotuberculosis/imunologia , Infecções por Yersinia pseudotuberculosis/microbiologia , Infecções por Yersinia pseudotuberculosis/patologia , Proteína rhoA de Ligação ao GTP/metabolismo
20.
Proc Natl Acad Sci U S A ; 113(33): E4857-66, 2016 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-27482109

RESUMO

Pyrin, encoded by the MEFV gene, is best known for its gain-of-function mutations causing familial Mediterranean fever (FMF), an autoinflammatory disease. Pyrin forms a caspase-1-activating inflammasome in response to inactivating modifications of Rho GTPases by various bacterial toxins or effectors. Pyrin-mediated innate immunity is unique in that it senses bacterial virulence rather than microbial molecules, but its mechanism of activation is unknown. Here we show that Pyrin was phosphorylated in bone marrow-derived macrophages and dendritic cells. We identified Ser-205 and Ser-241 in mouse Pyrin whose phosphorylation resulted in inhibitory binding by cellular 14-3-3 proteins. The two serines underwent dephosphorylation upon toxin stimulation or bacterial infection, triggering 14-3-3 dissociation, which correlated with Pyrin inflammasome activation. We developed antibodies specific for phosphorylated Ser-205 and Ser-241, which confirmed the stimuli-induced dephosphorylation of endogenous Pyrin. Mutational analyses indicated that both phosphorylation and signal-induced dephosphorylation of Ser-205/241 are important for Pyrin activation. Moreover, microtubule drugs, including colchicine, commonly used to treat FMF, effectively blocked activation of the Pyrin inflammasome. These drugs did not affect Pyrin dephosphorylation and 14-3-3 dissociation but inhibited Pyrin-mediated apoptosis-associated Speck-like protein containing CARD (ASC) aggregation. Our study reveals that site-specific (de)phosphorylation and microtubule dynamics critically control Pyrin inflammasome activation, illustrating a fine and complex mechanism in cytosolic immunity.


Assuntos
Inflamassomos/fisiologia , Microtúbulos/fisiologia , Pirina/metabolismo , Proteínas 14-3-3/metabolismo , Animais , Toxinas Bacterianas/farmacologia , Enterotoxinas/farmacologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Moduladores de Tubulina/farmacologia
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