Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.439
Filtrar
1.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360971

RESUMO

Interleukin-22 (IL-22) plays a role in epithelial barrier function and repair, and may provide benefits in conditions like inflammatory bowel disease. However, limited human data are available to assess the clinical effect of IL-22 administration. This study used a human intestinal cell line to identify an IL-22-dependent gene signature that could serve as a pharmacodynamic biomarker for IL-22 therapy. The response to IL-22Fc (UTTR1147A, an Fc-stabilized version of IL-22) was assessed in HT-29 cells by microarray, and the selected responsive genes were confirmed by qPCR. HT-29 cells demonstrated dose-dependent increases in STAT3 phosphorylation and multiple gene expression changes in response to UTTR1147A. Genes were selected that were upregulated by UTTR1147A, but to a lesser extent by IL-6, which also signals via STAT3. IL-1R1 was highly upregulated by UTTR1147A, and differential gene expression patterns were observed in response to IL-22Fc in the presence of IL-1ß. An IL-22-dependent gene signature was identified that could serve as a pharmacodynamic biomarker in intestinal biopsies to support the clinical development of an IL-22 therapeutic. The differential gene expression pattern in the presence of IL-1ß suggests that an inflammatory cytokine milieu in the disease setting could influence the clinical responses to IL-22.


Assuntos
Anti-Inflamatórios/farmacologia , Imunoglobulina G/genética , Doenças Inflamatórias Intestinais/metabolismo , Interleucinas/genética , Transcriptoma/efeitos dos fármacos , Biomarcadores/metabolismo , Células HT29 , Humanos , Imunoglobulina G/metabolismo , Interleucinas/metabolismo , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Fator de Transcrição STAT3/metabolismo
2.
Nature ; 595(7866): 266-271, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34163066

RESUMO

Obesity is a worldwide epidemic that predisposes individuals to many age-associated diseases, but its exact effects on organ dysfunction are largely unknown1. Hair follicles-mini-epithelial organs that grow hair-are miniaturized by ageing to cause hair loss through the depletion of hair follicle stem cells (HFSCs)2. Here we report that obesity-induced stress, such as that induced by a high-fat diet (HFD), targets HFSCs to accelerate hair thinning. Chronological gene expression analysis revealed that HFD feeding for four consecutive days in young mice directed activated HFSCs towards epidermal keratinization by generating excess reactive oxygen species, but did not reduce the pool of HFSCs. Integrative analysis using stem cell fate tracing, epigenetics and reverse genetics showed that further feeding with an HFD subsequently induced lipid droplets and NF-κB activation within HFSCs via autocrine and/or paracrine IL-1R signalling. These integrated factors converge on the marked inhibition of Sonic hedgehog (SHH) signal transduction in HFSCs, thereby further depleting lipid-laden HFSCs through their aberrant differentiation and inducing hair follicle miniaturization and eventual hair loss. Conversely, transgenic or pharmacological activation of SHH rescued HFD-induced hair loss. These data collectively demonstrate that stem cell inflammatory signals induced by obesity robustly represses organ regeneration signals to accelerate the miniaturization of mini-organs, and suggests the importance of daily prevention of organ dysfunction.


Assuntos
Alopecia/patologia , Alopecia/fisiopatologia , Folículo Piloso/patologia , Obesidade/fisiopatologia , Células-Tronco/patologia , Animais , Comunicação Autócrina , Contagem de Células , Diferenciação Celular , Linhagem da Célula , Senescência Celular , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Proteínas Hedgehog/metabolismo , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/patologia , Estresse Oxidativo , Comunicação Parácrina , Receptores de Interleucina-1/metabolismo
3.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066976

RESUMO

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor's fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1ß-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1ß-mediated crosstalk between both cell types. We silenced IL1ß in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1ß is overexpressed in cocultured tumor cells. IL1ß enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1ß-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFß1-driven NCFs. IL1ß induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1ß-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1ß-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Inflamação/patologia , Interleucina-1beta/metabolismo , Transdução de Sinais , Fibroblastos Associados a Câncer/patologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Interleucina-1beta/genética , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Interleucina-1/metabolismo , Ensaio Tumoral de Célula-Tronco
4.
Cell Death Dis ; 12(6): 575, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083516

RESUMO

Kawasaki disease (KD) is an acute vasculitis of pediatric populations that may develop coronary artery aneurysms if untreated. It has been regarded as the principal cause of acquired heart disease in children of the developed countries. Interleukin (IL)-37, as one of the IL-1 family members, is a natural suppressor of inflammation that is caused by activation of innate and adaptive immunity. However, detailed roles of IL-37 in KD are largely unclear. Sera from patients with KD displayed that IL-37 level was significantly decreased compared with healthy controls (HCs). QRT-PCR and western blot analyses showed that the expression level of IL-37 variant, IL-37b, was remarkably downregulated in human umbilical vein endothelial cells (HUVECs) exposed to KD sera-treated THP1 cells. Therefore, we researched the role of IL-37b in the context of KD and hypothesized that IL-37b may have a powerful protective effect in KD patients. We first observed and substantiated the protective role of IL-37b in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). In vitro experiments demonstrated that IL-37b alleviated endothelial cell apoptosis and inflammation via IL-1R8 receptor by inhibiting ERK and NFκB activation, which were also recapitulated in the KD mouse model. Together, our findings suggest that IL-37b play an effective protective role in coronary endothelial damage in KD, providing new evidence that IL-37b is a potential candidate drug to treat KD.


Assuntos
Interleucina-1/metabolismo , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/metabolismo , Receptores de Interleucina-1/metabolismo , Animais , Apoptose/fisiologia , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
5.
J Neuroimmunol ; 355: 577552, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33845282

RESUMO

A 43 year-old male presented with a relapsing and progressive systemic inflammatory disorder with central nervous system (CNS) involvement. After a two years follow up, he was diagnosed with hemophagocytic lymphohistiocytosis (HLH), based on clinical, laboratory and radiological findings. Treatment was started with anakinra, a recombinant humanised interleukin-1 (IL-1) receptor antagonist. Clinical response was good. Laboratory and radiological findings showed no disease activity throughout a five years follow-up period. Several immunosuppressive agents have been used in HLH without any good outcomes. This is the first case report of HLH with CNS involvement responsive to chronic treatment with anakinra.


Assuntos
Encéfalo/diagnóstico por imagem , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Linfo-Histiocitose Hemofagocítica/diagnóstico por imagem , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Nervos Espinhais/diagnóstico por imagem , Adulto , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Seguimentos , Humanos , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Linfo-Histiocitose Hemofagocítica/metabolismo , Masculino , Receptores de Interleucina-1/agonistas , Receptores de Interleucina-1/metabolismo , Recidiva , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/metabolismo , Resultado do Tratamento
6.
Life Sci ; 276: 119402, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785335

RESUMO

In our previous study, we observed that donor pulmonary intravascular nonclassical monocytes play a major role in early PGF, but the specific mechanism remained unclear. In this study, we investigated the mechanistic role of monocytes in inducing pyroptosis of human pulmonary microvascular endothelial cells (HPMECs) during IRI. A murine hilar ligation model of IRI was utilized whereby left lungs underwent 1 h of ischemia and 23 h of reperfusion. Monocyte depletion by intraperitoneal clodronate-liposome treatment on pulmonary edema and pyroptosis activation were determined. In vitro experiments, we performed the co-culture experiments under hypoxia-reoxygenation (H/R) conditions to mimic the IRI environment. We monitored the expression of NLRP3, caspase-1 and IL-1ß in co-cultures of monocytes (U937 cells) and HPMECs under H/R conditions. NLRP3, IL-1ß and IL-1R siRNA knockdown, caspase-1 and NF-κB pathway inhibitors were employed to elucidate the mechanism modulating HPMEC pyroptosis during H/R. Treatment of mice with clodronate-liposome attenuated IR-induced pulmonary edema, cytokine production and pyroptosis activation. In vitro, NLRP3 knockdown in monocytes reduced caspase-1 and IL-1ß secretion in co-cultures of monocytes and HPMECs. Reduced HPMEC pyroptosis was also observed either containing HPMECs with genetically engineered IL-1R knockdown or in co-culture treated with a Triplotide inhibitor that disrupts NF-κB signaling. Monocytes play a vital role in the development of transplant-associated ischemia-reperfusion injury. A potential role is that monocytes secrete IL-1ß to induce HPMEC pyroptosis via the IL-1R/NF-κB/NLRP3 pathway.


Assuntos
Endotélio Vascular/patologia , Inflamação/patologia , Pneumopatias/complicações , Monócitos/patologia , Piroptose , Traumatismo por Reperfusão/complicações , Doenças Vasculares/patologia , Animais , Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Humanos , Inflamassomos , Inflamação/etiologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Células U937 , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo
7.
Cancer Res ; 81(9): 2358-2372, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33619117

RESUMO

Macrophages are critical mediators of tissue homeostasis, cell proliferation, and tumor metastasis. Tumor-associated macrophages (TAM) are generally associated with tumor-promoting immunosuppressive functions in solid tumors. Here, we examined the transcriptional landscape of adaptor molecules downstream of Toll-like receptors in human cancers and found that higher expression of MYD88 correlated with tumor progression. In murine melanoma, MyD88, but not Trif, was essential for tumor progression, angiogenesis, and maintaining the immunosuppressive phenotype of TAMs. In addition, MyD88 expression in myeloid cells drove melanoma progression. The MyD88/IL1 receptor (IL1R) axis regulated programmed cell death (PD)-1 expression on TAMs by promoting recruitment of NF-κBp65 to the Pdcd1 promoter. Furthermore, a combinatorial immunotherapy approach combining the MyD88 inhibitor with anti-PD-1 blockade elicited strong antitumor effects. Thus, the MyD88/IL1R axis maintains the immunosuppressive function of TAMs and promotes tumor growth by regulating PD-1 expression. SIGNIFICANCE: These findings indicate that MyD88 regulates TAM-immunosuppressive activity, suggesting that macrophage-mediated immunotherapy combining MYD88 inhibitors with PD-1 blockade could result in better treatment outcomes in a wide variety of cancers. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2358/F1.large.jpg.


Assuntos
Tolerância Imunológica/genética , Melanoma/imunologia , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Interleucina-1/metabolismo , Transdução de Sinais/genética , Neoplasias Cutâneas/imunologia , Macrófagos Associados a Tumor/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/patologia , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Receptores de Interleucina-1/genética , Neoplasias Cutâneas/patologia
8.
Commun Biol ; 4(1): 172, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33558616

RESUMO

IL-36, which belongs to the IL-1 superfamily, is increasingly linked to neutrophilic inflammation. Here, we combined in vivo and in vitro approaches using primary mouse and human cells, as well as, acute and chronic mouse models of lung inflammation to provide mechanistic insight into the intercellular signaling pathways and mechanisms through which IL-36 promotes lung inflammation. IL-36 receptor deficient mice exposed to cigarette smoke or cigarette smoke and H1N1 influenza virus had attenuated lung inflammation compared with wild-type controls. We identified neutrophils as a source of IL-36 and show that IL-36 is a key upstream amplifier of lung inflammation by promoting activation of neutrophils, macrophages and fibroblasts through cooperation with GM-CSF and the viral mimic poly(I:C). Our data implicate IL-36, independent of other IL-1 family members, as a key upstream amplifier of neutrophilic lung inflammation, providing a rationale for targeting IL-36 to improve treatment of a variety of neutrophilic lung diseases.


Assuntos
Interleucina-1/metabolismo , Pulmão/metabolismo , Ativação de Neutrófilo , Neutrófilos/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Pneumonia Viral/metabolismo , Receptores de Interleucina-1/metabolismo , Animais , Células Cultivadas , Fumar Cigarros , Modelos Animais de Doenças , Feminino , Fibroblastos/imunologia , Fibroblastos/metabolismo , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Interleucina-1/genética , Pulmão/imunologia , Pulmão/virologia , Ativação de Macrófagos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/virologia , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptores de Interleucina-1/genética , Transdução de Sinais
9.
Front Immunol ; 12: 631044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33613576

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has been raging around the world since January 2020. Pregnancy places the women in a unique immune scenario which may allow severe COVID-19 disease. In this regard, the potential unknown effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on mothers and fetuses have attracted considerable attention. There is no clear consistent evidence of the changes in the immune status of pregnant women after recovery from COVID-19. In this study, we use multiparameter flow cytometry and Luminex assay to determine the immune cell subsets and cytokines, respectively, in the peripheral blood and umbilical cord blood from pregnant women recovering from COVID-19 about 3 months (n=5). Our results showed decreased percentages of Tc2, Tfh17, memory B cells, virus-specific NK cells, and increased percentages of naive B cells in the peripheral blood. Serum levels of IL-1ra and MCP-1 showed a decreased tendency in late recovery stage (LRS) patients. Meanwhile, there was no significant difference in immune cell subsets in the umbilical cord blood. The placentas from LRS patients showed increased CD68+ macrophages infiltration and mild hypoxic features. The inflammatory damage of the placenta may be related to the antiviral response. Since the receptors, ACE2 and TMPRSS2, utilized by SARS-CoV-2 are not co-expressed in the placenta, so it is extremely rare for SARS-CoV-2 to cause infection through this route and the impact on the fetus is negligible.


Assuntos
Linfócitos B/imunologia , COVID-19/imunologia , Sangue Fetal/imunologia , Centro Germinativo/imunologia , Placenta/imunologia , SARS-CoV-2/fisiologia , Células Th17/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Autoantígenos/metabolismo , Feminino , Citometria de Fluxo , Humanos , Memória Imunológica , Imunofenotipagem , Células Matadoras Naturais , Gravidez , Receptores de Interleucina-1/metabolismo , Serina Endopeptidases/metabolismo
10.
Theranostics ; 11(1): 1-13, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391457

RESUMO

Background: Interleukin 37 (IL-37), a member of IL-1 family, broadly suppresses inflammation in many pathological conditions by acting as a dual-function cytokine in that IL-37 signals via the extracellular receptor complex IL1-R5/IL-1R8, but it can also translocate to the nucleus. However, whether IL-37 exerts beneficial actions in neuroinflammatory diseases, such as multiple sclerosis, remains to be elucidated. Thus, the goals of the present study were to evaluate the therapeutic effects of IL-37 in a mouse model of multiple sclerosis, and if so, whether this is mediated via the extracellular receptor complex IL-1R5/IL-1R8. Methods: We used a murine model of MS, the experimental autoimmune encephalomyelitis (EAE). We induced EAE in three different single and double transgenic mice (hIL-37tg, IL-1R8 KO, hIL-37tg-IL-1R8 KO) and wild type littermates. We also induced EAE in C57Bl/6 mice and treated them with various forms of recombinant human IL-37 protein. Functional and histological techniques were used to assess locomotor deficits and demyelination. Luminex and flow cytometry analysis were done to assess the protein levels of pro-inflammatory cytokines and different immune cell populations, respectively. qPCRs were done to assess the expression of IL-37, IL-1R5 and IL-1R8 in the spinal cord of EAE, and in blood peripheral mononuclear cells and brain tissue samples of MS patients. Results: We demonstrate that IL-37 reduces inflammation and protects against neurological deficits and myelin loss in EAE mice by acting via IL1-R5/IL1-R8. We also reveal that administration of recombinant human IL-37 exerts therapeutic actions in EAE mice. We finally show that IL-37 transcripts are not up-regulated in peripheral blood mononuclear cells and in brain lesions of MS patients, despite the IL-1R5/IL-1R8 receptor complex is expressed. Conclusions: This study presents novel data indicating that IL-37 exerts therapeutic effects in EAE by acting through the extracellular receptor complex IL-1R5/IL-1R8, and that this protective physiological mechanism is defective in MS individuals. IL-37 may therefore represent a novel therapeutic avenue for the treatment of MS with great promising potential.


Assuntos
Encéfalo/metabolismo , Encefalomielite Autoimune Experimental/genética , Interleucina-1/genética , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , Receptores de Interleucina-1/genética , Medula Espinal/metabolismo , Adulto , Idoso , Animais , Encéfalo/patologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Feminino , Humanos , Inflamação , Interleucina-1/farmacologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/metabolismo , Esclerose Múltipla Recidivante-Remitente/metabolismo , Receptores de Interleucina-1/metabolismo , Medula Espinal/patologia
11.
Immunology ; 163(2): 145-154, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33501638

RESUMO

Interleukin 36 (IL-36) constitutes a group of cytokines that belong to the IL-1 superfamily. Emerging evidence has suggested a role of IL-36 in the pathogenesis of many inflammatory disorders. Intriguingly, in the gastrointestinal tract, IL-36 has a rather complex function. IL-36 receptor ligands are overexpressed in both animal colitis models and human IBD patients and may play both pathogenic and protective roles, depending on the context. IL-36 cytokines comprise three receptor agonists: IL-36α, IL-36ß and IL-36γ, and two receptor antagonists: IL-36Ra and IL-38. All IL-36 receptor agonists bind to the IL-36R complex and exert pleiotropic effects during inflammatory settings. Here, we first briefly review the processing and secretion of IL-36 cytokines. We then focus on the current understanding of the immunology effects of IL-36 in gut immunity. In addition, we also discuss the ongoing trials that aim to blockage IL-36R signalling for treating chronic intestinal inflammation and present some unexplored questions regarding IL-36 research.


Assuntos
Colite/imunologia , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-1/metabolismo , Mucosa Intestinal/imunologia , Animais , Modelos Animais de Doenças , Humanos , Interleucinas/metabolismo , Terapia de Alvo Molecular , Receptores de Interleucina-1/metabolismo , Transdução de Sinais
12.
Brain Behav Immun ; 91: 181-193, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002631

RESUMO

While the original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis, the role of its ortholog Toll-like receptors (TLRs), the interleukin 1 receptor (IL-1R) family, and the associated signaling pathways in mammalian brain development and structure is poorly understood. Because the adaptor protein myeloid differentiation primary response protein 88 (MyD88) is essential for downstream signaling of most TLRs and IL-1R, we systematically investigated the effect of MyD88 deficiency on murine brain structure during development and on behavior. In neonatal Myd88-/- mice, neocortical thickness was reduced, while density of cortical neurons was increased. In contrast, microglia, astrocyte, oligodendrocyte, and proliferating cell numbers were unchanged in these mice compared to wild-type mice. In adult Myd88-/- mice, neocortical thickness was unaltered, but neuronal density in neocortex and hippocampus was increased. Neuron arborization was less pronounced in adult Myd88-/- mice compared to wild-type animals. In addition, numbers of microglia and proliferating cells were increased in the neocortex and subventricular zone, respectively, with unaltered astrocyte and oligodendrocyte numbers, and myelinization was enhanced in the adult Myd88-/- neocortex. These morphologic changes in the brain of adult Myd88-/- mice were accompanied by specific behavioral traits, such as decreased locomotor activity, increased anxiety-like behavior, but normal day/light activity, satisfactory learning, short- and long-term spatial memory, potential cognitive inflexibility, and increased hanging and locomotor behavior within their home cage. Taken together, MyD88 deficiency results in morphologic and cellular changes in the mouse brain, as well as in altered natural and specific behaviors. Our data indicate a pathophysiological significance of MyD88 for mammalian CNS development, structure, and function.


Assuntos
Comportamento Animal , Encéfalo/patologia , Fator 88 de Diferenciação Mieloide , Proteínas Adaptadoras de Transdução de Sinal , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores de Interleucina-1/metabolismo
13.
Int J Mol Sci ; 21(22)2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33202693

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life "American lifestyle-induced obesity syndrome" (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r-/-- but not Il-1r-/- mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.


Assuntos
Interleucina-18/metabolismo , Interleucina-1/metabolismo , Fígado/lesões , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais , Animais , Interleucina-1/genética , Interleucina-18/genética , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-18/genética , Receptores de Interleucina-18/metabolismo
14.
Front Immunol ; 11: 569127, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072109

RESUMO

Toll-like receptors (TLRs) are at the forefront of pathogen recognition ensuring host fitness and eliciting protective cellular and humoral responses. Signaling pathways downstream of TLRs are tightly regulated for preventing collateral damage and loss of tolerance toward commensals. To trigger effective intracellular signaling, these receptors require the involvement of adaptor proteins. Among these, Toll/Interleukin-1 receptor domain containing adaptor protein (Tirap or MAL) plays an important role in establishing immune responses. Loss of function of MAL was associated with either disease susceptibility or resistance. These opposite effects reveal paradoxical functions of MAL and their importance in containing infectious or non-infectious diseases. In this review, we summarize the current knowledge on the signaling pathways involving MAL in different pathologies and their impact on inducing protective or non-protective responses.


Assuntos
Suscetibilidade a Doenças , Glicoproteínas de Membrana/metabolismo , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Animais , Proteínas de Transporte/metabolismo , Endossomos/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Imunomodulação , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Ligação Proteica , Proteólise , Receptores de Interleucina-1/química , Receptores de Interleucina-1/genética , Relação Estrutura-Atividade , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
15.
Proc Natl Acad Sci U S A ; 117(44): 27540-27548, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33087566

RESUMO

Enteropathogenic bacterial infections are a global health issue associated with high mortality, particularly in developing countries. Efficient host protection against enteropathogenic bacterial infection is characterized by coordinated responses between immune and nonimmune cells. In response to infection in mice, innate immune cells are activated to produce interleukin (IL)-23 and IL-22, which promote antimicrobial peptide (AMP) production and bacterial clearance. IL-36 cytokines are proinflammatory IL-1 superfamily members, yet their role in enteropathogenic bacterial infection remains poorly defined. Using the enteric mouse pathogen, C. rodentium, we demonstrate that signaling via IL-36 receptor (IL-36R) orchestrates a crucial innate-adaptive immune link to control bacterial infection. IL-36R-deficient mice (Il1rl2 -/- ) exhibited significant impairment in expression of IL-22 and AMPs, increased intestinal damage, and failed to contain C. rodentium compared to controls. These defects were associated with failure to induce IL-23 and IL-6, two key IL-22 inducers in the early and late phases of infection, respectively. Treatment of Il1rl2 -/- mice with IL-23 during the early phase of C. rodentium infection rescued IL-22 production from group 3 innate lymphoid cells (ILCs), whereas IL-6 administration during the late phase rescued IL-22-mediated production from CD4+ T cell, and both treatments protected Il1rl2 -/- mice from uncontained infection. Furthermore, IL-36R-mediated IL-22 production by CD4+ T cells was dependent upon NFκB-p65 and IL-6 expression in dendritic cells (DCs), as well as aryl hydrocarbon receptor (AhR) expression by CD4+ T cells. Collectively, these data demonstrate that the IL-36 signaling pathway integrates innate and adaptive immunity leading to host defense against enteropathogenic bacterial infection.


Assuntos
Imunidade Adaptativa , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Imunidade Inata , Receptores de Interleucina-1/metabolismo , Animais , Citrobacter rodentium/patogenicidade , Modelos Animais de Doenças , Infecções por Enterobacteriaceae/microbiologia , Interleucina-1/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Knockout , Receptores de Interleucina-1/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia
16.
Mol Med Rep ; 22(4): 2851-2859, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32945488

RESUMO

Single immunoglobulin and Toll­interleukin­1 receptor domain­containing molecule (SIGIRR) is a specific inhibitor of IL­1R and Toll­like receptor (TLR) signaling and considered a potential target for the treatment of inflammatory diseases. Pathogenic mechanisms associated with the TLR4 signaling pathway have a critical role in the development of severe acute pancreatitis (SAP). The aim of the present study was to determine the role of SIGIRR in the regulation of TLR4 signaling during the progression of SAP. Pancreatitis­associated ascitic fluid (PAAF) was collected from patients with SAP. Murine RAW264.7 macrophages were transfected with a SIGIRR overexpression plasmid and co­cultured with the PAAF from the donors in order to evaluate the effect of SIGIRR in vitro. The mRNA expression of TLR4, SIGIRR and other key downstream signaling molecules was quantified using semi­quantitative PCR with agarose gel electrophoresis. Furthermore, the levels of pro­inflammatory cytokines in the culture supernatant were detected using ELISA. In contrast to SIGIRR, the mRNA expression levels of TLR4, myeloid differentiation factor 88 (MyD88), IL­1R­associated kinase­1 (IRAK­1) and TNF receptor­associated factor­6 (TRAF­6) were significantly increased in RAW264.7 cells following treatment with PAAF. Furthermore, TLR4, MyD88, IRAK­1 and TRAF­6 mRNA levels were significantly downregulated following SIGIRR overexpression and PAAF treatment in RAW264.7 cells. The levels of IL­2, IL­12, IL­17 and IFN­Î³ in the culture supernatant were also significantly decreased, while IL­10 levels were increased. Overall, SIGIRR negatively regulated the TLR4 signaling pathway to protect against the development of SAP in an in vitro model. Therefore, SIGIRR may represent a promising therapeutic target for SAP.


Assuntos
Macrófagos/metabolismo , Pancreatite/metabolismo , Receptores de Interleucina-1/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/genética , Receptor 4 Toll-Like/metabolismo , Animais , Líquido Ascítico/metabolismo , Técnicas de Cocultura , Citocinas/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Células RAW 264.7 , RNA Mensageiro , Receptores de Interleucina-1/genética , Transfecção
17.
Sci Rep ; 10(1): 15724, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973293

RESUMO

Cachexia is a progressive muscle wasting disease that contributes to death in a wide range of chronic diseases. Currently, the cachexia field lacks animal models that recapitulate the long-term kinetics of clinical disease, which would provide insight into the pathophysiology of chronic cachexia and a tool to test therapeutics for disease reversal. Toxoplasma gondii (T. gondii) is a protozoan parasite that uses conserved mechanisms to infect rodents and human hosts. Infection is lifelong and has been associated with chronic weight loss and muscle atrophy in mice. We have recently shown that T. gondii-induced muscle atrophy meets the clinical definition of cachexia. Here, the longevity of the T. gondii-induced chronic cachexia model revealed that cachectic mice develop perivascular fibrosis in major metabolic organs, including the adipose tissue, skeletal muscle, and liver by 9 weeks post-infection. Development of cachexia, as well as liver and skeletal muscle fibrosis, is dependent on intact signaling through the type I IL-1R receptor. IL-1α is sufficient to activate cultured fibroblasts and primary hepatic stellate cells (myofibroblast precursors in the liver) in vitro, and IL-1α is elevated in the sera and liver of cachectic, suggesting a mechanism by which chronic IL-1R signaling could be leading to cachexia-associated fibrosis.


Assuntos
Caquexia/parasitologia , Cirrose Hepática/parasitologia , Músculo Esquelético/parasitologia , Receptores de Interleucina-1/metabolismo , Toxoplasmose/complicações , Animais , Caquexia/metabolismo , Caquexia/patologia , Modelos Animais de Doenças , Fibrose/metabolismo , Fibrose/patologia , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Interleucina-1alfa/farmacologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Atrofia Muscular/parasitologia , Atrofia Muscular/patologia , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Transdução de Sinais/fisiologia , Toxoplasmose/metabolismo , Toxoplasmose/patologia
18.
Sci Rep ; 10(1): 15831, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985578

RESUMO

The Toll-interleukin 1 receptor superfamily includes the genes interleukin 1 receptor-like 1 (IL1RL1), Toll like receptors (TLRs), myeloid differentiation primary-response 88 (MyD88), and MyD88 adaptor-like (TIRAP). This study describes the interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection. Cases and controls were genotyped at the polymorphic sites MyD88 rs6853, TIRAP rs8177374 and IL1RL1 rs11123923. The results show that specific combinations of IL1RL1-TIRAP (AA-CT; P: 2,8 × 10-17) and MyD88-TIRAP-IL1RL1 (AA-CT-AA; P: 1,4 × 10-8) - but not MyD88 alone-act synergistically against Helicobacter pylori. Nuclear magnetic resonance (NMR) clearly discriminates cases from controls by highlighting significantly different expression levels of several metabolites (tyrosine, tryptophan, phenylalanine, branched-chain amino acids, short chain fatty acids, glucose, sucrose, urea, etc.). NMR also identifies the following dysregulated metabolic pathways associated to Helicobacter pylori infection: phenylalanine and tyrosine metabolism, pterine biosynthesis, starch and sucrose metabolism, and galactose metabolism. Furthermore, NMR discriminates between the cases heterozygous at the IL1RL1 locus from those homozygous at the same locus. Heterozygous patients are characterized by high levels of lactate, and IL1RL1-both associated with anti-inflammatory activity-and low levels of the pro-inflammatory molecules IL-1ß, TNF-α, COX-2, and IL-6.


Assuntos
Infecções por Helicobacter/metabolismo , Helicobacter pylori , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Glicoproteínas de Membrana/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores de Interleucina-1/metabolismo , Resistência à Doença/genética , Infecções por Helicobacter/genética , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Espectroscopia de Ressonância Magnética , Glicoproteínas de Membrana/genética , Fator 88 de Diferenciação Mieloide/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Interleucina-1/genética
19.
J Med Chem ; 63(22): 13316-13329, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32931267

RESUMO

Myeloid differentiation primary response protein 88 (MyD88) is a ubiquitously expressed cytoplasmic adaptor protein that plays a central role in the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways. TLR/IL-1R pathways regulate the proliferation and differentiation of cells involved in the innate and adaptive immunity. Although the general TLR/IL-1R activation cascade is well understood, the molecular mechanisms involving MyD88 have only begun to surface in the past decade. In this review, we explore MyD88 structural biology, the role of posttranslational modifications (PTMs), and the recent developments in MyD88 inhibitor discovery and use. We also highlight the potential application of MyD88-targeted therapies in human diseases.


Assuntos
Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores de Interleucina-1/metabolismo , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo , Sequência de Aminoácidos , Animais , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Humanos , Fator 88 de Diferenciação Mieloide/química , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/fisiologia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores de Interleucina-1/química , Transdução de Sinais/efeitos dos fármacos , Tiazóis/química , Tiazóis/metabolismo , Tiazóis/farmacologia , Receptores Toll-Like/química
20.
Int J Mol Sci ; 21(18)2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899668

RESUMO

Tissue fibrosis is a major unresolved medical problem, which impairs the function of various systems. The molecular mechanisms involved are poorly understood, which hinders the development of effective therapeutic strategies. Emerging evidence from recent studies indicates that interleukin 36 (IL-36) and the corresponding receptor (IL-36R), a newly-characterized cytokine/receptor signaling complex involved in immune-inflammation, play an important role in the pathogenesis of fibrosis in multiple tissues. This review focuses on recent experimental findings, which implicate IL-36R and its associated cytokines in different forms of organ fibrosis. Specifically, it outlines the molecular basis and biological function of IL-36R in normal cells and sums up the pathological role in the development of fibrosis in the lung, kidney, heart, intestine, and pancreas. We also summarize the new progress in the IL-36/IL-36R-related mechanisms involved in tissue fibrosis and enclose the potential of IL-36R inhibition as a therapeutic strategy to combat pro-fibrotic pathologies. Given its high association with disease, gaining new insight into the immuno-mechanisms that contribute to tissue fibrosis could have a significant impact on human health.


Assuntos
Interleucina-1/imunologia , Interleucina-1/metabolismo , Receptores de Interleucina-1/metabolismo , Citocinas/imunologia , Fibrose/imunologia , Humanos , Inflamação/patologia , Interleucinas/imunologia , Receptores de Interleucina-1/genética , Transdução de Sinais/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...