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1.
Cell ; 187(15): 3885-3887, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39059365

RESUMO

Immunosenescence poses a significant challenge to tumor immunotherapy in elderly individuals. In this issue of Cell, Zhivaki et al. elucidate that dendritic cells "hyperactivated" by specific adjuvants elicit TH1-skewed CD4+ T cell responses in a manner contingent on the NLRP3 inflammasome, which can eliminate tumors in aged mice.


Assuntos
Células Dendríticas , Animais , Células Dendríticas/imunologia , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Inflamassomos/imunologia , Imunoterapia/métodos , Linfócitos T CD4-Positivos/imunologia , Humanos , Envelhecimento/imunologia , Células Th1/imunologia , Imunossenescência
2.
Cell ; 186(10): 2144-2159.e22, 2023 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-37172565

RESUMO

Bats are special in their ability to live long and host many emerging viruses. Our previous studies showed that bats have altered inflammasomes, which are central players in aging and infection. However, the role of inflammasome signaling in combating inflammatory diseases remains poorly understood. Here, we report bat ASC2 as a potent negative regulator of inflammasomes. Bat ASC2 is highly expressed at both the mRNA and protein levels and is highly potent in inhibiting human and mouse inflammasomes. Transgenic expression of bat ASC2 in mice reduced the severity of peritonitis induced by gout crystals and ASC particles. Bat ASC2 also dampened inflammation induced by multiple viruses and reduced mortality of influenza A virus infection. Importantly, it also suppressed SARS-CoV-2-immune-complex-induced inflammasome activation. Four key residues were identified for the gain of function of bat ASC2. Our results demonstrate that bat ASC2 is an important negative regulator of inflammasomes with therapeutic potential in inflammatory diseases.


Assuntos
Proteínas Reguladoras de Apoptose , Quirópteros , Inflamassomos , Ribonucleoproteínas , Viroses , Animais , Humanos , Camundongos , Proteínas Reguladoras de Apoptose/metabolismo , Quirópteros/imunologia , COVID-19 , Inflamassomos/imunologia , Ribonucleoproteínas/metabolismo , SARS-CoV-2 , Viroses/imunologia , Fenômenos Fisiológicos Virais
3.
Cell ; 181(3): 674-687.e13, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32298652

RESUMO

Caspases regulate cell death, immune responses, and homeostasis. Caspase-6 is categorized as an executioner caspase but shows key differences from the other executioners. Overall, little is known about the functions of caspase-6 in biological processes apart from apoptosis. Here, we show that caspase-6 mediates innate immunity and inflammasome activation. Furthermore, we demonstrate that caspase-6 promotes the activation of programmed cell death pathways including pyroptosis, apoptosis, and necroptosis (PANoptosis) and plays an essential role in host defense against influenza A virus (IAV) infection. In addition, caspase-6 promoted the differentiation of alternatively activated macrophages (AAMs). Caspase-6 facilitated the RIP homotypic interaction motif (RHIM)-dependent binding of RIPK3 to ZBP1 via its interaction with RIPK3. Altogether, our findings reveal a vital role for caspase-6 in facilitating ZBP1-mediated inflammasome activation, cell death, and host defense during IAV infection, opening additional avenues for treatment of infectious and autoinflammatory diseases and cancer.


Assuntos
Caspase 6/imunologia , Caspase 6/metabolismo , Inflamassomos/imunologia , Animais , Apoptose/imunologia , Morte Celular/imunologia , Imunidade Inata , Inflamassomos/metabolismo , Inflamassomos/fisiologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Necroptose/imunologia , Ligação Proteica , Piroptose/imunologia , Proteínas de Ligação a RNA/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
4.
Nat Immunol ; 23(2): 165-176, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35105981

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, continues to cause substantial morbidity and mortality. While most infections are mild, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm and acute respiratory distress syndrome. The innate immune system acts as the first line of defense, sensing the virus through pattern recognition receptors and activating inflammatory pathways that promote viral clearance. Here, we discuss innate immune processes involved in SARS-CoV-2 recognition and the resultant inflammation. Improved understanding of how the innate immune system detects and responds to SARS-CoV-2 will help identify targeted therapeutic modalities that mitigate severe disease and improve patient outcomes.


Assuntos
COVID-19/imunologia , Imunidade Inata , SARS-CoV-2/imunologia , Animais , COVID-19/metabolismo , COVID-19/virologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Evasão da Resposta Imune , Inflamassomos/imunologia , Inflamassomos/metabolismo , Proteínas NLR/imunologia , Proteínas NLR/metabolismo , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , SARS-CoV-2/patogenicidade , Transdução de Sinais , Receptores Toll-Like/imunologia , Receptores Toll-Like/metabolismo , Internalização do Vírus
5.
Nat Immunol ; 22(5): 550-559, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33707781

RESUMO

The NLRP3 inflammasome is a multimeric cytosolic protein complex that assembles in response to cellular perturbations. This assembly leads to the activation of caspase-1, which promotes maturation and release of the inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18, as well as inflammatory cell death (pyroptosis). The inflammatory cytokines contribute to the development of systemic low-grade inflammation, and aberrant NLRP3 activation can drive a chronic inflammatory state in the body to modulate the pathogenesis of inflammation-associated diseases. Therefore, targeting NLRP3 or other signaling molecules downstream, such as caspase-1, IL-1ß or IL-18, has the potential for great therapeutic benefit. However, NLRP3 inflammasome-mediated inflammatory cytokines play dual roles in mediating human disease. While they are detrimental in the pathogenesis of inflammatory and metabolic diseases, they have a beneficial role in numerous infectious diseases and some cancers. Therefore, fine tuning of NLRP3 inflammasome activity is essential for maintaining proper cellular homeostasis and health. In this Review, we will cover the mechanisms of NLRP3 inflammasome activation and its divergent roles in the pathogenesis of inflammation-associated diseases such as cancer, atherosclerosis, diabetes and obesity, highlighting the therapeutic potential of targeting this pathway.


Assuntos
Inflamassomos/metabolismo , Doenças Metabólicas/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias/metabolismo , Animais , Citocinas/metabolismo , Humanos , Inflamassomos/imunologia , Doenças Metabólicas/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Neoplasias/imunologia , Transdução de Sinais , Microambiente Tumoral
6.
Nat Immunol ; 22(4): 412-422, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33603227

RESUMO

A fundamental concept in immunology is that the innate immune system initiates or instructs downstream adaptive immune responses. Inflammasomes are central players in innate immunity to pathogens, but how inflammasomes shape adaptive immunity is complex and relatively poorly understood. Here we highlight recent work on the interplay between inflammasomes and adaptive immunity. We address how inflammasome-dependent release of cytokines and antigen activates, shapes or even inhibits adaptive immune responses. We consider how distinct tissue or cellular contexts may alter the effects of inflammasome activation on adaptive immunity and how this contributes to beneficial or detrimental outcomes in infectious diseases, cancer and autoimmunity. We aspire to provide a framework for thinking about inflammasomes and their connection to the adaptive immune response.


Assuntos
Imunidade Adaptativa , Antígenos/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Inflamassomos/metabolismo , Animais , Antígenos/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/metabolismo , Citocinas/imunologia , Humanos , Inflamassomos/imunologia , Ativação Linfocitária , Neoplasias/imunologia , Neoplasias/metabolismo , Piroptose , Transdução de Sinais , Vacinação
7.
Annu Rev Immunol ; 29: 707-35, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21219188

RESUMO

Inflammasome activation leads to caspase-1 activation, which causes the maturation and secretion of pro-IL-1ß and pro-IL-18 among other substrates. A subgroup of the NLR (nucleotide-binding domain, leucine-rich repeat containing) proteins are key mediators of the inflammasome. Studies of gene-deficient mice and cells have implicated NLR inflammasomes in a host of responses to a wide range of microbial pathogens, inflammatory diseases, cancer, and metabolic and autoimmune disorders. Determining exactly how the inflammasome is activated in these diseases and disease models remains a challenge. This review presents and integrates recent progress in the field.


Assuntos
Inflamassomos/imunologia , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Animais , Humanos , Mediadores da Inflamação/imunologia , Doenças Metabólicas/imunologia , Neoplasias/imunologia
8.
Cell ; 175(6): 1651-1664.e14, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30392956

RESUMO

The activator and composition of the NLRP6 inflammasome remain poorly understood. We find that lipoteichoic acid (LTA), a molecule produced by Gram-positive bacteria, binds and activates NLRP6. In response to cytosolic LTA or infection with Listeria monocytogenes, NLRP6 recruited caspase-11 and caspase-1 via the adaptor ASC. NLRP6 activation by LTA induced processing of caspase-11, which promoted caspase-1 activation and interleukin-1ß (IL-1ß)/IL-18 maturation in macrophages. Nlrp6-/- and Casp11-/- mice were less susceptible to L. monocytogenes infection, which was associated with reduced pathogen loads and impaired IL-18 production. Administration of IL-18 to Nlrp6-/- or Casp11-/- mice restored the susceptibility of mutant mice to L. monocytogenes infection. These results reveal a previously unrecognized innate immunity pathway triggered by cytosolic LTA that is sensed by NLRP6 and exacerbates systemic Gram-positive pathogen infection via the production of IL-18.


Assuntos
Imunidade Inata , Inflamassomos/imunologia , Lipopolissacarídeos/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Receptores de Superfície Celular/imunologia , Ácidos Teicoicos/imunologia , Animais , Caspase 1/genética , Caspase 1/imunologia , Caspases/genética , Caspases/imunologia , Caspases Iniciadoras , Inflamassomos/genética , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Listeriose/genética , Listeriose/patologia , Camundongos , Camundongos Knockout , Receptores de Superfície Celular/genética
9.
Nat Immunol ; 21(8): 880-891, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32541830

RESUMO

Bacterial lipopolysaccharide triggers human caspase-4 (murine caspase-11) to cleave gasdermin-D and induce pyroptotic cell death. How lipopolysaccharide sequestered in the membranes of cytosol-invading bacteria activates caspases remains unknown. Here we show that in interferon-γ-stimulated cells guanylate-binding proteins (GBPs) assemble on the surface of Gram-negative bacteria into polyvalent signaling platforms required for activation of caspase-4. Caspase-4 activation is hierarchically controlled by GBPs; GBP1 initiates platform assembly, GBP2 and GBP4 control caspase-4 recruitment, and GBP3 governs caspase-4 activation. In response to cytosol-invading bacteria, activation of caspase-4 through the GBP platform is essential to induce gasdermin-D-dependent pyroptosis and processing of interleukin-18, thereby destroying the replicative niche for intracellular bacteria and alerting neighboring cells, respectively. Caspase-11 and GBPs epistatically protect mice against lethal bacterial challenge. Multiple antagonists of the pathway encoded by Shigella flexneri, a cytosol-adapted bacterium, provide compelling evolutionary evidence for the importance of the GBP-caspase-4 pathway in antibacterial defense.


Assuntos
Caspases Iniciadoras/imunologia , Proteínas de Ligação ao GTP/imunologia , Infecções por Bactérias Gram-Negativas/imunologia , Inflamassomos/imunologia , Transdução de Sinais/imunologia , Animais , Bactérias Gram-Negativas/imunologia , Células HeLa , Humanos , Lipopolissacarídeos/imunologia , Camundongos , Piroptose/imunologia
10.
Nat Immunol ; 21(1): 65-74, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31848486

RESUMO

The cytokine interleukin (IL)-1ß is a key mediator of antimicrobial immunity as well as autoimmune inflammation. Production of IL-1ß requires transcription by innate immune receptor signaling and maturational cleavage by inflammasomes. Whether this mechanism applies to IL-1ß production seen in T cell-driven autoimmune diseases remains unclear. Here, we describe an inflammasome-independent pathway of IL-1ß production that was triggered upon cognate interactions between effector CD4+ T cells and mononuclear phagocytes (MPs). The cytokine TNF produced by activated CD4+ T cells engaged its receptor TNFR on MPs, leading to pro-IL-1ß synthesis. Membrane-bound FasL, expressed by CD4+ T cells, activated death receptor Fas signaling in MPs, resulting in caspase-8-dependent pro-IL-1ß cleavage. The T cell-instructed IL-1ß resulted in systemic inflammation, whereas absence of TNFR or Fas signaling protected mice from CD4+ T cell-driven autoimmunity. The TNFR-Fas-caspase-8-dependent pathway provides a mechanistic explanation for IL-1ß production and its consequences in CD4+ T cell-driven autoimmune pathology.


Assuntos
Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Inflamação/patologia , Interleucina-1beta/metabolismo , Células Mieloides/metabolismo , Animais , Caspase 1/genética , Caspase 8/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Proteína Ligante Fas/metabolismo , Imunidade Inata/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Nat Immunol ; 21(1): 30-41, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819254

RESUMO

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.


Assuntos
Injúria Renal Aguda/imunologia , Apolipoproteína C-III/imunologia , Caspase 8/metabolismo , Nefropatias/imunologia , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Injúria Renal Aguda/patologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apolipoproteína C-III/genética , Linhagem Celular , Modelos Animais de Doenças , Células HEK293 , Humanos , Inflamassomos/imunologia , Inflamação/genética , Inflamação/imunologia , Nefropatias/patologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
12.
Nat Immunol ; 21(8): 857-867, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601469

RESUMO

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by homozygous or compound heterozygous gain-of-function mutations in MEFV, which encodes pyrin, an inflammasome protein. Heterozygous carrier frequencies for multiple MEFV mutations are high in several Mediterranean populations, suggesting that they confer selective advantage. Among 2,313 Turkish people, we found extended haplotype homozygosity flanking FMF-associated mutations, indicating evolutionarily recent positive selection of FMF-associated mutations. Two pathogenic pyrin variants independently arose >1,800 years ago. Mutant pyrin interacts less avidly with Yersinia pestis virulence factor YopM than with wild-type human pyrin, thereby attenuating YopM-induced interleukin (IL)-1ß suppression. Relative to healthy controls, leukocytes from patients with FMF harboring homozygous or compound heterozygous mutations and from asymptomatic heterozygous carriers released heightened IL-1ß specifically in response to Y. pestis. Y. pestis-infected MefvM680I/M680I FMF knock-in mice exhibited IL-1-dependent increased survival relative to wild-type knock-in mice. Thus, FMF mutations that were positively selected in Mediterranean populations confer heightened resistance to Y. pestis.


Assuntos
Resistência à Doença/genética , Febre Familiar do Mediterrâneo/genética , Peste , Pirina/genética , Seleção Genética/genética , Animais , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas da Membrana Bacteriana Externa/metabolismo , Resistência à Doença/imunologia , Haplótipos , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Peste/imunologia , Peste/metabolismo , Pirina/imunologia , Pirina/metabolismo , Turquia , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo , Yersinia pestis
13.
Cell ; 168(3): 544-544.e1, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28129545

RESUMO

This SnapShot depicts how the noncanonical inflammasome pathway is initiated and activated, as well as its effector mechanism in triggering pyroptosis and immune defenses.


Assuntos
Infecções/imunologia , Inflamassomos/imunologia , Animais , Caspases/metabolismo , Humanos , Imunidade Inata , Infecções/metabolismo , Inflamassomos/metabolismo , Transdução de Sinais
14.
Cell ; 168(3): 503-516.e12, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-28129542

RESUMO

Sickness-induced anorexia is a conserved behavior induced during infections. Here, we report that an intestinal pathogen, Salmonella Typhimurium, inhibits anorexia by manipulating the gut-brain axis. Inhibition of inflammasome activation by the S. Typhimurium effector, SlrP, prevented anorexia caused by IL-1ß-mediated signaling to the hypothalamus via the vagus nerve. Rather than compromising host defenses, pathogen-mediated inhibition of anorexia increased host survival. SlrP-mediated inhibition of anorexia prevented invasion and systemic infection by wild-type S. Typhimurium, reducing virulence while increasing transmission to new hosts, suggesting that there are trade-offs between transmission and virulence. These results clarify the complex and contextual role of anorexia in host-pathogen interactions and suggest that microbes have evolved mechanisms to modulate sickness-induced behaviors to promote health of their host and their transmission at the expense of virulence.


Assuntos
Anorexia/microbiologia , Infecções por Salmonella/microbiologia , Infecções por Salmonella/transmissão , Salmonella typhimurium/patogenicidade , Animais , Proteínas de Bactérias/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais , Infecções por Salmonella/imunologia , Salmonella typhimurium/fisiologia , Organismos Livres de Patógenos Específicos , Virulência
15.
Cell ; 171(5): 1057-1071.e11, 2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-29033131

RESUMO

Type I interferon restrains interleukin-1ß (IL-1ß)-driven inflammation in macrophages by upregulating cholesterol-25-hydroxylase (Ch25h) and repressing SREBP transcription factors. However, the molecular links between lipid metabolism and IL-1ß production remain obscure. Here, we demonstrate that production of 25-hydroxycholesterol (25-HC) by macrophages is required to prevent inflammasome activation by the DNA sensor protein absent in melanoma 2 (AIM2). We find that in response to bacterial infection or lipopolysaccharide (LPS) stimulation, macrophages upregulate Ch25h to maintain repression of SREBP2 activation and cholesterol synthesis. Increasing macrophage cholesterol content is sufficient to trigger IL-1ß release in a crystal-independent but AIM2-dependent manner. Ch25h deficiency results in cholesterol-dependent reduced mitochondrial respiratory capacity and release of mitochondrial DNA into the cytosol. AIM2 deficiency rescues the increased inflammasome activity observed in Ch25h-/-. Therefore, activated macrophages utilize 25-HC in an anti-inflammatory circuit that maintains mitochondrial integrity and prevents spurious AIM2 inflammasome activation.


Assuntos
Colesterol/metabolismo , Inflamassomos/metabolismo , Macrófagos/metabolismo , Animais , Colesterol/biossíntese , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Hidroxicolesteróis/metabolismo , Inflamassomos/imunologia , Inflamação/imunologia , Inflamação/patologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Listeria monocytogenes/fisiologia , Listeriose/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Mitocôndrias/metabolismo , Oxisteróis/metabolismo
16.
Nat Immunol ; 20(5): 559-570, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30996332

RESUMO

The C-type lectin receptor-Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans. The cytokine IL-1ß served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1ß and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1ß, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1ß and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host-pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/imunologia , Candidíase/imunologia , Quimiocina CXCL1/imunologia , Interleucina-1beta/imunologia , Microglia/imunologia , Neutrófilos/imunologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/microbiologia , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Candida albicans/imunologia , Candida albicans/fisiologia , Candidíase/genética , Candidíase/microbiologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Microglia/metabolismo , Microglia/microbiologia , Infiltração de Neutrófilos/genética , Infiltração de Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia
17.
Cell ; 165(4): 792-800, 2016 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-27153493

RESUMO

Canonical activation of the inflammasome is critical to promote caspase-1-dependent maturation of the proinflammatory cytokines IL-1ß and IL-18, as well as to induce pyroptotic cell death in response to pathogens and endogenous danger signals. Recent discoveries, however, are beginning to unveil new components of the inflammasome machinery as well as the full spectrum of inflammasome functions, extending their influence beyond canonical functions to regulation of eicosanoid storm, autophagy, and metabolism. In addition, the receptor components of the inflammasome can also regulate diverse biological processes, such as cellular proliferation, gene transcription, and tumorigenesis, all of which are independent of their inflammasome complex-forming capabilities. Here, we review these recent advances that are shaping our understanding of the complex biology of the inflammasome and its constituents.


Assuntos
Inflamassomos/fisiologia , Transdução de Sinais , Animais , Morte Celular , Humanos , Inflamassomos/imunologia , Inflamação/imunologia , Inflamação/metabolismo
18.
Cell ; 165(3): 656-67, 2016 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-27085913

RESUMO

The earliest events following mucosal HIV-1 infection, prior to measurable viremia, remain poorly understood. Here, by detailed necropsy studies, we show that the virus can rapidly disseminate following mucosal SIV infection of rhesus monkeys and trigger components of the inflammasome, both at the site of inoculation and at early sites of distal virus spread. By 24 hr following inoculation, a proinflammatory signature that lacked antiviral restriction factors was observed in viral RNA-positive tissues. The early innate response included expression of NLRX1, which inhibits antiviral responses, and activation of the TGF-ß pathway, which negatively regulates adaptive immune responses. These data suggest a model in which the virus triggers specific host mechanisms that suppress the generation of antiviral innate and adaptive immune responses in the first few days of infection, thus facilitating its own replication. These findings have important implications for the development of vaccines and other strategies to prevent infection.


Assuntos
Inflamassomos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Animais , Medula Óssea/imunologia , Imunidade Inata , Imunidade nas Mucosas , Células Matadoras Naturais/imunologia , Macaca mulatta , Proteínas Mitocondriais/metabolismo , Monócitos/imunologia , Linfócitos T/imunologia , Transcriptoma , Fator de Crescimento Transformador beta/metabolismo , Replicação Viral
19.
Cell ; 167(2): 382-396.e17, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27693356

RESUMO

The inflammasome is an intracellular signaling complex, which on recognition of pathogens and physiological aberration, drives activation of caspase-1, pyroptosis, and the release of the pro-inflammatory cytokines IL-1ß and IL-18. Bacterial ligands must secure entry into the cytoplasm to activate inflammasomes; however, the mechanisms by which concealed ligands are liberated in the cytoplasm have remained unclear. Here, we showed that the interferon-inducible protein IRGB10 is essential for activation of the DNA-sensing AIM2 inflammasome by Francisella novicida and contributed to the activation of the LPS-sensing caspase-11 and NLRP3 inflammasome by Gram-negative bacteria. IRGB10 directly targeted cytoplasmic bacteria through a mechanism requiring guanylate-binding proteins. Localization of IRGB10 to the bacterial cell membrane compromised bacterial structural integrity and mediated cytosolic release of ligands for recognition by inflammasome sensors. Overall, our results reveal IRGB10 as part of a conserved signaling hub at the interface between cell-autonomous immunity and innate immune sensing pathways.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Francisella/imunologia , GTP Fosfo-Hidrolases/metabolismo , Infecções por Bactérias Gram-Negativas/imunologia , Interações Hospedeiro-Patógeno/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Linfócitos B/imunologia , Caspases/metabolismo , Caspases Iniciadoras , Citosol/imunologia , Citosol/microbiologia , GTP Fosfo-Hidrolases/genética , Infecções por Bactérias Gram-Negativas/microbiologia , Imunidade Celular , Imunidade Inata , Inflamassomos/metabolismo , Ligantes , Camundongos , Camundongos Mutantes , Células Mieloides/imunologia , Linfócitos T/imunologia
20.
Cell ; 167(2): 444-456.e14, 2016 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-27716507

RESUMO

While conventional pathogenic protists have been extensively studied, there is an underappreciated constitutive protist microbiota that is an integral part of the vertebrate microbiome. The impact of these species on the host and their potential contributions to mucosal immune homeostasis remain poorly studied. Here, we show that the protozoan Tritrichomonas musculis activates the host epithelial inflammasome to induce IL-18 release. Epithelial-derived IL-18 promotes dendritic cell-driven Th1 and Th17 immunity and confers dramatic protection from mucosal bacterial infections. Along with its role as a "protistic" antibiotic, colonization with T. musculis exacerbates the development of T-cell-driven colitis and sporadic colorectal tumors. Our findings demonstrate a novel mutualistic host-protozoan interaction that increases mucosal host defenses at the cost of an increased risk of inflammatory disease.


Assuntos
Colite/imunologia , Colite/parasitologia , Interações Hospedeiro-Parasita , Inflamassomos/imunologia , Mucosa Intestinal/parasitologia , Microbiota/imunologia , Tricomoníase/imunologia , Trichomonas/imunologia , Animais , Colite/microbiologia , Dientamoeba/imunologia , Imunidade nas Mucosas , Interleucina-18/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Simbiose , Células Th1/imunologia , Células Th17/imunologia
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