Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
Immunity ; 54(6): 1137-1153.e8, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34051146

RESUMO

Alterations in the cGAS-STING DNA-sensing pathway affect intestinal homeostasis. We sought to delineate the functional role of STING in intestinal inflammation. Increased STING expression was a feature of intestinal inflammation in mice with colitis and in humans afflicted with inflammatory bowel disease. Mice bearing an allele rendering STING constitutively active exhibited spontaneous colitis and dysbiosis, as well as progressive chronic intestinal inflammation and fibrosis. Bone marrow chimera experiments revealed STING accumulation in intestinal macrophages and monocytes as the initial driver of inflammation. Depletion of Gram-negative bacteria prevented STING accumulation in these cells and alleviated intestinal inflammation. STING accumulation occurred at the protein rather than transcript level, suggesting post-translational stabilization. We found that STING was ubiquitinated in myeloid cells, and this K63-linked ubiquitination could be elicited by bacterial products, including cyclic di-GMP. Our findings suggest a positive feedback loop wherein dysbiosis foments the accumulation of STING in intestinal myeloid cells, driving intestinal inflammation.


Assuntos
Colite/imunologia , Disbiose/imunologia , Imunidade Inata/imunologia , Proteínas de Membrana/imunologia , Células Mieloides/imunologia , Ubiquitinação/imunologia , Animais , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/imunologia , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia
2.
PLoS Pathog ; 15(8): e1007990, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425553

RESUMO

The granulomatous lesion resulting from infection with the fungus Paracoccidioides brasiliensis is characterized by a compact aggregate of mature cells, surrounded by a fibroblast- and collagen-rich content. Granuloma formation requires signaling elicited by inflammatory molecules such as members of the interleukin-1 family. Two members of this family have been thoroughly studied, namely IL-1α and IL-1ß. In this study, we addressed the mechanisms underlying IL-1α secretion and its functional role on the host resistance to fungal infection. We found that, the expression of caspase-11 triggered by P. brasiliensis infection of macrophages depends on IFN-ß production, because its inhibition reduced procaspase-11 levels. Curiously, caspase-11 deficiency did not impair IL-1ß production, however caspase-11 was required for a rapid pore-mediated cell lysis. The plasma membrane rupture facilitated the release of IL-1α, which was necessary to induce NO production and restrict fungal replication. Furthermore, P. brasiliensis-infected macrophages required IL-1α to produce optimal levels of IL-6, a major component of Th17 lymphocyte differentiation. Indeed, IL-1α deficiency accounted for a significant reduction of Th17 lymphocytes in lungs of infected mice, correlating with diminished neutrophil infiltration in the lungs. Strikingly, we identified that IL-1α directly reprograms the transcriptional profile of Th17-committed lymphocytes, increasing cellular proliferation, as for boosting IL-17 production by these cells. Beyond neutrophil chemotaxis in vivo, IL-17 also amplified IL-1α production by infected macrophages in vitro, endorsing a critical amplification loop of the inflammatory response. Therefore, our data suggest that the IFN-ß/caspase-11/IL-1α pathway shapes a protective antifungal Th17 immunity, revealing a molecular mechanism underlying the cross-talk between innate and adaptive immunity.


Assuntos
Caspases/fisiologia , Imunidade Inata/imunologia , Interleucina-1alfa/metabolismo , Macrófagos/imunologia , Paracoccidioides/imunologia , Paracoccidioidomicose/imunologia , Células Th17/imunologia , Animais , Caspases Iniciadoras , Inflamassomos , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Paracoccidioidomicose/metabolismo , Paracoccidioidomicose/microbiologia , Células Th17/metabolismo , Células Th17/microbiologia
3.
J Infect Dis ; 217(2): 329-339, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29099934

RESUMO

Background: Paracoccidioides brasiliensis is equipped with an arsenal of virulence factors that are crucial for causing infection. Our group previously defined the NLRP3 inflammasome as a mediator of P brasiliensis-induced cell damage recognition and induction of effective Th1 immune responses. However, deficiency of caspase-1 only partially reduced interleukin (IL)-1ß levels. Methods: In this study, using chemical inhibitors as well as genetically modified mice, we identify an additional pathway for IL-1ß production in response to P brasiliensis infection. Results: Paracoccidioides brasiliensis initiated caspase-8-mediated IL-1ß production, an event that was necessary for transcriptional priming and posttranslational processing of pro-IL-1ß. Caspase-8 synergizes with the canonical NLRP3 inflammasome pathway to control caspase-1 processing and IL-1ß maturation, providing a regulatory role for caspase-8 in host resistance to in vivo P brasiliensis infection. Conclusions: Taken together, these findings revealed an important role for caspase-8 in the innate immune response of host cells to P brasiliensis infection, demonstrating a connected network between noncanonical and canonical inflammasomes to coordinate IL-1ß production during fungal challenge.


Assuntos
Caspase 1/metabolismo , Caspase 8/metabolismo , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Paracoccidioides/imunologia , Paracoccidioidomicose/imunologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/parasitologia , Redes Reguladoras de Genes , Imunidade Inata , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Macrófagos/parasitologia , Camundongos Endogâmicos C57BL
4.
J Immunol ; 194(9): 4507-17, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25825440

RESUMO

Pathogens are sensed by innate immune receptors that initiate an efficient adaptive immune response upon activation. The elements of the innate immune recognition process for Paracoccidioides brasiliensis include TLR-2, TLR-4, and dectin-1. However, there are additional receptors necessary for the host immune responses to P. brasiliensis. The nucleotide-binding oligomerization domain-like receptor (NLRs), which activate inflammasomes, are candidate receptors that deserve renewed investigation. After pathogen infection, the NLRs form large signaling platforms called inflammasomes, which lead to caspase-1 activation and maturation of proinflammatory cytokines (IL-18 and IL-1ß). In this study, we showed that NLR family pyrin domain-containing 3 (Nlrp3) is required to induce caspase-1 activation and further secretion of IL-1ß and IL-18 by P. brasiliensis-infected macrophages. Additionally, potassium efflux and lysosomal acidification induced by the fungus were important steps in the caspase-1 activation mechanism. Notably, Nlrp3 and caspase-1 knockout mice were more susceptible to infection than were the wild-type animals, suggesting that the Nlrp3-dependent inflammasomes contribute to host protection against P. brasiliensis. This protective effect occurred owing to the inflammatory response mediated by IL-18, as shown by an augmented fungus burden in IL-18 knockout mice. Taken together, our results show that the Nlrp3 inflammasome is essential for resistance against P. brasiliensis because it orchestrates robust caspase-1 activation and triggers an IL-18-dependent proinflammatory response.


Assuntos
Proteínas de Transporte/metabolismo , Imunidade Inata , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/metabolismo , Animais , Caspase 1/metabolismo , Modelos Animais de Doenças , Resistência à Doença/genética , Resistência à Doença/imunologia , Granuloma/genética , Granuloma/imunologia , Granuloma/metabolismo , Inflamassomos/genética , Interleucina-18/genética , Interleucina-1beta/biossíntese , Pneumopatias Fúngicas/mortalidade , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Paracoccidioides/imunologia
5.
J Mol Biol ; 434(4): 167378, 2022 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-34838807

RESUMO

Cell death is an essential process in all living organisms and occurs through different mechanisms. The three main types of programmed cell death are apoptosis, pyroptosis, and necroptosis, and each of these pathways employs complex molecular and cellular mechanisms. Although there are mechanisms and outcomes specific to each pathway, they share common components and features. In this review, we discuss recent discoveries in these three best understood modes of cell death, highlighting their singularities, and examining the intriguing notion that common players shape different individual pathways in this highly interconnected and coordinated cell death system. Understanding the similarities and differences of these cell death processes is crucial to enable targeted strategies to manipulate these pathways for therapeutic benefit.


Assuntos
Apoptose , Necroptose , Piroptose , Animais , Humanos
6.
J Exp Med ; 219(8)2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35792863

RESUMO

Hepatocyte nuclear factor 4 α (HNF4A) is a highly conserved nuclear receptor that has been associated with ulcerative colitis. In mice, HNF4A is indispensable for the maintenance of intestinal homeostasis, yet the underlying mechanisms are poorly characterized. Here, we demonstrate that the expression of HNF4A in intestinal epithelial cells (IECs) is required for the proper development and composition of the intraepithelial lymphocyte (IEL) compartment. HNF4A directly regulates expression of immune signaling molecules including butyrophilin-like (Btnl) 1, Btnl6, H2-T3, and Clec2e that control IEC-IEL crosstalk. HNF4A selectively enhances the expansion of natural IELs that are TCRγδ+ or TCRαß+CD8αα+ to shape the composition of IEL compartment. In the small intestine, HNF4A cooperates with its paralog HNF4G, to drive expression of immune signaling molecules. Moreover, the HNF4A-BTNL regulatory axis is conserved in human IECs. Collectively, these findings underscore the importance of HNF4A as a conserved transcription factor controlling IEC-IEL crosstalk and suggest that HNF4A maintains intestinal homeostasis through regulation of the IEL compartment.


Assuntos
Linfócitos Intraepiteliais , Animais , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Mucosa Intestinal , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
7.
iScience ; 24(6): 102548, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34142053

RESUMO

The recognition of fungi by intracellular NOD-like receptors (NLRs) induces inflammasome assembly and activation. Although the NLRC4 inflammasome has been extensively studied in bacterial infections, its role during fungal infections is unclear. Paracoccidioidomycosis (PCM) is a pathogenic fungal disease caused by Paracoccidioides brasiliensis. Here, we show that NLRC4 confers susceptibility to experimental PCM by regulating NLRP3-dependent cytokine production and thus protective effector mechanisms. Early after infection, NLRC4 suppresses prostaglandin E2 production, and consequently reduces interleukin (IL)-1ß release by macrophages and dendritic cells in the lungs. IL-1ß is required to control fungal replication via induction of the nitric oxide synthase 2 (NOS2) pathway. At a later stage of the disease, NLRC4 impacts IL-18 release, dampening robust CD8+IFN-γ+ T cell responses and enhancing mortality of mice. These findings demonstrate that NLRC4 promotes disease by regulating the production of inflammatory cytokines and cellular responses that depend on the NLRP3 inflammasome activity.

8.
Curr Biol ; 30(12): R689-R694, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32574626

RESUMO

Ketelut-Carneiro and Fitzgerald discuss the basic concepts about inflammasome composition, assembly and activation, effector functions and role in infection and inflammatory disease.


Assuntos
Inflamassomos/metabolismo , Animais , Humanos , Inflamassomos/imunologia
9.
Science ; 369(6511): 1633-1637, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32820063

RESUMO

Activated macrophages undergo a metabolic switch to aerobic glycolysis, accumulating Krebs' cycle intermediates that alter transcription of immune response genes. We extended these observations by defining fumarate as an inhibitor of pyroptotic cell death. We found that dimethyl fumarate (DMF) delivered to cells or endogenous fumarate reacts with gasdermin D (GSDMD) at critical cysteine residues to form S-(2-succinyl)-cysteine. GSDMD succination prevents its interaction with caspases, limiting its processing, oligomerization, and capacity to induce cell death. In mice, the administration of DMF protects against lipopolysaccharide shock and alleviates familial Mediterranean fever and experimental autoimmune encephalitis by targeting GSDMD. Collectively, these findings identify GSDMD as a target of fumarate and reveal a mechanism of action for fumarate-based therapeutics that include DMF, for the treatment of multiple sclerosis.


Assuntos
Cisteína/análogos & derivados , Fumarato de Dimetilo/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Esclerose Múltipla/tratamento farmacológico , Proteínas de Ligação a Fosfato/metabolismo , Piroptose/efeitos dos fármacos , Animais , Caspases/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Cisteína/metabolismo , Fumarato de Dimetilo/uso terapêutico , Feminino , Células HEK293 , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lipopolissacarídeos/imunologia , Ativação de Macrófagos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Proteínas de Ligação a Fosfato/genética , Processamento de Proteína Pós-Traducional , Piroptose/imunologia
10.
Front Immunol ; 8: 949, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28871251

RESUMO

Paracoccidioidomycosis (PCM), a chronic granulomatous disease caused by the thermally dimorphic fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii, has the highest mortality rate among systemic mycosis. The T helper 1-mediated immunity is primarily responsible for acquired resistance during P. brasiliensis infection, while susceptibility is associated with Th2 occurrence. Th17 is a population of T CD4+ cells that, among several chemokines and cytokines, produces IL-17A and requires the presence of IL-1, IL-6, and TGF-ß for differentiation in mice and IL-23 for its maintenance. Th17 has been described as an arm of the immune system that enhances host protection against several bacterial and fungal infections, as Pneumocystis carinii and Candida albicans. In this study, we aimed to evaluate the Th17 immune response and the role of Th17-associated cytokines (IL-6, IL-23, and IL-17A) during experimental PCM. First, we observed that P. brasiliensis infection [virulent yeast strain 18 of P. brasiliensis (Pb18)] increased the IL-17A production in vitro and all the evaluated Th17-associated cytokines in the lung tissue from C57BL/6 wild-type mice. In addition, the deficiency of IL-6, IL-23, or IL-17 receptor A (IL-17RA) impaired the compact granuloma formation and conferred susceptibility during infection, associated with reduced tumor necrosis factor-α, IFN-γ, and inducible nitric oxide synthase enzyme expression. Our data suggest that IL-6 production by bone marrow-derived macrophages (BMDMs) is important to promote the Th17 differentiation during Pb18 infection. In accordance, the adoptive transfer of BMDMs from C57BL/6 to infected IL-6-/- or IL-17RA-/- mice reduced the fungal burden in the lungs compared to nontransferred mice and reestablished the pulmonary granuloma formation. Taken together, these results suggest that Th17-associated cytokines are involved in the modulation of immune response and granuloma formation during experimental PCM.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA