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1.
Sci Immunol ; 5(51)2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989174

RESUMO

Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in the circulation of patients with active disease paired with strong activation. Furthermore, transcriptomic analyses indicated significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69high and CXCR3low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and later release back into the circulation when disease is resolved. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their possible involvement in COVID-19 immunopathogenesis.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Células T Invariáveis Associadas à Mucosa/imunologia , Pneumonia Viral/patologia , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Infecções por Coronavirus/imunologia , Feminino , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-17/metabolismo , Lectinas Tipo C/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Receptores CXCR3/metabolismo , Adulto Jovem
2.
Nat Commun ; 11(1): 4368, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868758

RESUMO

Increased extracellular sodium activates Th17 cells, which provide protection from bacterial and fungal infections. Whilst high salt diets have been shown to worsen autoimmune disease, the immunological consequences of clinical salt depletion are unknown. Here, we investigate immunity in patients with inherited salt-losing tubulopathies (SLT). Forty-seven genotyped SLT patients (with Bartter, Gitelman or EAST Syndromes) are recruited. Clinical features of dysregulated immunity are recorded with a standardised questionnaire and immunological investigations of IL-17 responsiveness undertaken. The effects of altering extracellular ionic concentrations on immune responses are then assessed. Patients are hypokalaemic and hypomagnesaemic, with reduced interstitial sodium stores determined by 23Na-magnetic resonance imaging. SLT patients report increased mucosal infections and allergic disease compared to age-matched controls. Aligned with their clinical phenotype, SLT patients have an increased ratio of Th2:Th17 cells. SLT Th17 and Tc17 polarisation is reduced in vitro, yet STAT1 and STAT3 phosphorylation and calcium flux following T cell activation are unaffected. In control cells, the addition of extracellular sodium (+40 mM), potassium (+2 mM), or magnesium (+1 mM) reduces Th2:Th17 ratio and augments Th17 polarisation. Our results thus show that the ionic environment typical in SLT impairs IL-17 immunity, but the intracellular pathways that mediate salt-driven Th17 polarisation are intact and in vitro IL-17 responses can be reinvigorated by increasing extracellular sodium concentration. Whether better correction of extracellular ions can rescue the immunophenotype in vivo in SLT patients remains unknown.


Assuntos
Síndromes de Imunodeficiência/etiologia , Interleucina-17/metabolismo , Túbulos Renais Distais/patologia , Adolescente , Adulto , Idoso de 80 Anos ou mais , Animais , Pré-Escolar , Doença Crônica , Estudos de Coortes , Feminino , Doenças Genéticas Inatas , Humanos , Magnésio/metabolismo , Masculino , Pessoa de Meia-Idade , Potássio/metabolismo , Sais/metabolismo , Sais/uso terapêutico , Sódio/metabolismo , Cloreto de Sódio/metabolismo , Cloreto de Sódio na Dieta/uso terapêutico , Células Th17/metabolismo , Células Th2/metabolismo , Adulto Jovem
3.
Proc Natl Acad Sci U S A ; 117(32): 19408-19414, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719138

RESUMO

Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F, and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T cells themselves, but not through their action on CD8+ T cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T cells to induce suppressive resistance, and this resistance can be reversed by blockade of IL-1ß, IL-6, or STAT3. These studies reveal a role for IL-17 cytokines in mediating CD4-intrinsic immune resistance. The pathways induced in this process may serve as a critical target for future investigation and immunotherapeutic intervention.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Humanos , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia
4.
Life Sci ; 258: 118137, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712299

RESUMO

AIMS: Chagas disease is a neglected tropical disease. The ability of Trypanosoma cruzi to survive within phagocytes is likely a critical factor for T. cruzi dissemination in the host. For control of the parasite load and host survival, macrophage action is required. Concanavalin-A (Con-A) presents properties that modulate immune functions and protect hosts from several experimental infectious diseases. Here, we evaluated the effects of Con-A on peritoneal macrophages as well as on the course of experimental infection by T. cruzi. MAIN METHODS: BALB/c mice, a susceptible model for T. cruzi infection, were treated with Con-A via the intraperitoneal route and 3 days later infected with T. cruzi. We quantified parasitemia, cytokines and nitric oxide (NO). Peritoneal exudate and macrophages were collected for macrophage phenotyping and cell viability, NO and cytokine detection, as well as for T. cruzi internalization and release index determination. KEY FINDINGS: Con-A treatment induced IL-17a and NO production by cells from the peritoneal cavity, and M1 marker expression predominated on peritoneal macrophages. These cells are also more prone to producing TNF-α, IL-6 and NO when infected by T. cruzi and show high trypanocidal capacity. Due to a hostile peritoneal microenvironment caused by Con-A, which induces macrophage cNOS and iNOS expression, infected BALB/c mice showed reduced parasitemia and an increased survival rate. SIGNIFICANCE: We conclude that Con-A can induce peritoneal M1 macrophage polarization to increase trypanocidal activity, resulting in ameliorated systemic infection in a susceptible experimental model.


Assuntos
Polaridade Celular , Doença de Chagas/patologia , Concanavalina A/farmacologia , Interleucina-17/metabolismo , Macrófagos Peritoneais/patologia , Macrófagos Peritoneais/parasitologia , Óxido Nítrico/metabolismo , Trypanosoma cruzi/fisiologia , Animais , Polaridade Celular/efeitos dos fármacos , Doença de Chagas/metabolismo , Feminino , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Parasitemia/metabolismo , Parasitemia/patologia , Trypanosoma cruzi/efeitos dos fármacos
5.
Nat Commun ; 11(1): 3334, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620760

RESUMO

TH17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of TH17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-ß signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in TH17 cells. Our data thus indicate a key function of TH17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of TH17 cells with regard to environmental changes.


Assuntos
Homeostase/imunologia , Inflamação/imunologia , Interleucina-10/imunologia , Intestinos/imunologia , Células Th17/imunologia , Animais , Plasticidade Celular/imunologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Células HEK293 , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/fisiologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo
6.
J Immunol ; 205(4): 892-898, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32651218

RESUMO

SARS-CoV-2, the virus causing COVID-19, has infected millions and has caused hundreds of thousands of fatalities. Risk factors for critical illness from SARS-CoV-2 infection include male gender, obesity, diabetes, and age >65. The mechanisms underlying the susceptibility to critical illness are poorly understood. Of interest, these comorbidities have previously been associated with increased signaling of Th17 cells. Th17 cells secrete IL-17A and are important for clearing extracellular pathogens, but inappropriate signaling has been linked to acute respiratory distress syndrome. Currently there are few treatment options for SARS-CoV-2 infections. This review describes evidence linking risk factors for critical illness in COVID-19 with increased Th17 cell activation and IL-17 signaling that may lead to increased likelihood for lung injury and respiratory failure. These findings provide a basis for testing the potential use of therapies directed at modulation of Th17 cells and IL-17A signaling in the treatment of COVID-19.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Interleucina-17/antagonistas & inibidores , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Células Th17/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/efeitos adversos , Comorbidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Estado Terminal , Feminino , Humanos , Interleucina-17/metabolismo , Masculino , Pandemias , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Síndrome do Desconforto Respiratório do Adulto/virologia , Fatores de Risco , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Th17/imunologia
7.
J Pharmacol Sci ; 144(2): 69-75, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32713799

RESUMO

The mechanism of the papaverine (PV) for the treatment of cerebral ischemia remains unclear. A total of 42 mice induced with focal cerebral ischemia were randomly divided into three groups: PV,baicalin (BA)and vehicle group. Both PV and BA could significantly reduce the ischemic infarct volume (P < 0.05). Pathway enrichment analysis was performed on MetaCore™ to search the molecular pathways associated with the gene expression profile of PV, compared with vehicle and BA. Compared with vehicle, we found that 60% of the top 10 pathways in PV group were related to immune response. The top 10 biological processes of the targeted pathways were mainly related to the multiple immunomodulatory process of neuro-vascular inflammation, including immune_Th17-deried cytokins, regulation of angiogenesis, cell adhesion_Leucocyte chemotaxis, antigen presentation, cell adhesion_synaptic contact, and inflammation related to Amphoterin signaling. Moreover, compared with BA, 17 pathways of PV were identified, and 58.82% (10/17) were also related to immune response, especially, half of the top 10 pathways with the lower p-value. In these top 10 pathways, 4 were the cytokine-mediated signaling pathways, which play key role in inflammation, like IL-17 signaling pathways with the activation of G-CSF,IL-23,RANKL, p38MAPK and NF-κB.These findings indicate that PV may be an efficacious pluripotent anti-inflammatory agent against cerebral ischemic-reperfusion injury by targeting on multiple immunomodulatory process of neuro-vascular inflammation.


Assuntos
Anti-Inflamatórios , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Fatores Imunológicos , Papaverina/farmacologia , Papaverina/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/genética , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Inflamação , Interleucina-17/genética , Interleucina-17/metabolismo , Masculino , Camundongos Endogâmicos , NF-kappa B/genética , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
8.
Nat Commun ; 11(1): 2859, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503973

RESUMO

Mature double negative (DN) T cells are a population of αß T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8+ T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.


Assuntos
Autoantígenos/imunologia , Interleucina-17/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Autoantígenos/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Tolerância Imunológica , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/metabolismo
9.
Nat Commun ; 11(1): 2856, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503977

RESUMO

Type I interferon (IFN-I) and T helper 17 (TH17) drive pathology in neuromyelitis optica spectrum disorder (NMOSD) and in TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE). This is paradoxical because the prevalent theory is that IFN-I inhibits TH17 function. Here we report that a cascade involving IFN-I, IL-6 and B cells promotes TH17-mediated neuro-autoimmunity. In NMOSD, elevated IFN-I signatures, IL-6 and IL-17 are associated with severe disability. Furthermore, IL-6 and IL-17 levels are lower in patients on anti-CD20 therapy. In mice, IFN-I elevates IL-6 and exacerbates TH17-EAE. Strikingly, IL-6 blockade attenuates disease only in mice treated with IFN-I. By contrast, B-cell-deficiency attenuates TH17-EAE in the presence or absence of IFN-I treatment. Finally, IFN-I stimulates B cells to produce IL-6 to drive pathogenic TH17 differentiation in vitro. Our data thus provide an explanation for the paradox surrounding IFN-I and TH17 in neuro-autoimmunity, and may have utility in predicting therapeutic response in NMOSD.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interferon Tipo I/imunologia , Neuromielite Óptica/imunologia , Células Th17/imunologia , Adulto , Animais , Autoimunidade , Linfócitos B/imunologia , Linfócitos B/metabolismo , Encefalomielite Autoimune Experimental/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Neuromielite Óptica/genética , Proteômica
10.
PLoS One ; 15(6): e0234493, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32520953

RESUMO

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination and inflammation. Dysregulated lipid metabolism and mitochondrial dysfunction are hypothesized to play a key role in MS. Carnitine Palmitoyl Transferase 1 (CPT1) is a rate-limiting enzyme for beta-oxidation of fatty acids in mitochondria. The therapeutic effect of pharmacological CPT1 inhibition with etomoxir was investigated in rodent models of myelin oligodendrocyte glycoprotein- and myelin basic protein-induced experimental autoimmune encephalitis (EAE). Mice receiving etomoxir showed lower clinical score compared to placebo, however this was not significant. Rats receiving etomoxir revealed significantly lower clinical score and lower body weight compared to placebo group. When comparing etomoxir with interferon-ß (IFN-ß), IFN-ß had no significant therapeutic effects, whereas etomoxir treatment starting at day 1 and 5 significantly improved the clinical scores compared to the IFN-ß and the placebo group. Immunohistochemistry and image assessments of brain sections from rats with EAE showed higher myelination intensity and decreased expression of CPT1A in etomoxir-treated rats compared to placebo group. Moreover, etomoxir mediated increased interleukin-4 production and decreased interleukin-17α production in activated T cells. In conclusion, CPT1 is a key protein in the pathogenesis of EAE and MS and a crucial therapeutic target for the treatment.


Assuntos
Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/farmacologia , Feminino , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Ratos , Ratos Endogâmicos Lew
11.
PLoS Negl Trop Dis ; 14(6): e0008386, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32542003

RESUMO

Chromoblastomycosis (CBM) is a chronic worldwide subcutaneous mycosis, caused by several dimorphic, pigmented dematiaceous fungi. It is difficult to treat patients with the disease, mainly because of its recalcitrant nature. The correct activation of host immune response is critical to avoid fungal persistence in the tissue and disease chronification. CD4+ T cells are crucial for the development of protective immunity to F. pedrosoi infection. Here, we investigated T helper cell response dynamics during experimental CBM. Following footpad injection with F. pedrosoi hyphae and conidia, T cells were skewed towards a Th17 and Th1 phenotype. The Th17 population was the main Th cell subset found in the infected area during the early stages of experimental murine CBM, followed by Th1 predominance in the later stages, coinciding with the remission phase of the disease in this experimental model. Depletion of CD25+ cells, which leads to a reduction of Treg cells in the draining lymph node, resulted in decline in fungal burden after 14 days of infection. However, fungal cells were not cleared in the later stages of the disease, prolonging CBM clinical features in those animals. IL-17A and IFN-γ neutralization hindered fungal cell elimination in the course of the disease. Similarly, in dectin-2 KO animals, Th17 contraction in the course of experimental CBM was accompanied by fungal burden decrease in the first 14 days of infection, although it did not affect disease resolution. In this study, we gained insight into T helper subsets' dynamics following footpad injections of F. pedrosoi propagules and uncovered their contribution to disease resolution. The Th17 population proved to be important in eliminating fungal cells in the early stages of infection. The Th1 population, in turn, closely assisted by Treg cells, proved to be relevant not only in the elimination of fungal cells at the beginning of infection but also essential for their complete elimination in later stages of the disease in a mouse experimental model of CBM.


Assuntos
Ascomicetos/imunologia , Cromoblastomicose/imunologia , Lectinas Tipo C/metabolismo , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Cromoblastomicose/microbiologia , Cromoblastomicose/patologia , Modelos Animais de Doenças , Humanos , Hifas , Interferon gama/metabolismo , Interleucina-17/metabolismo , Lectinas Tipo C/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esporos Fúngicos
12.
Am J Med Sci ; 360(2): 176-191, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32553747

RESUMO

BACKGROUND: This study aimed to investigate the role of Clostridium butyricum (C. butyricum) in conjunction with the Toll-like receptor2 (TLR2) signaling pathway and T helper 17 (Th17) cells in dextran sodium sulfate (DSS)-induced colitis in mice. METHODS: Forty 8-week-old BALB/c mice were randomly divided into 5 groups of 8 mice for 7 days: control, DSS (5% DSS), DSS+C. butyricum (1 × 109 CFU), DSS+C. butyricum (1 × 108 CFU) and DSS+C. butyricum (1 × 107 CFU) groups. We assessed the disease activity index (DAI) and histological damage scores. The expression levels of TLR2, myeloid differentiation factor 88 (MyD88), nuclear factor kappa-B p65 (NF-κBp65), interleukin (IL) 17 (IL17), IL23 and retineic acid receptor related orphan nuclear receptor gamma t (RORγt) were determined through immunohistochemical staining, western blot and quantitative real-time PCR (qRT-PCR). The expression levels of CD3+CD4+IL17+ cells in peripheral blood were measured by flow cytometry. RESULTS: C. butyricum dose-dependently decreased DAI and histological damage scores in DSS mice and down-regulated the mRNA and protein levels of TLR2, MyD88 and NF-κBp65 in mouse colon tissue (all P < 0.05). In addition, C. butyricum dose-dependently decreased the levels of CD3+CD4+IL17+ cells in peripheral blood and down-regulated the mRNA and protein levels of IL17, IL23 and RORγt in mouse colon tissue (all P < 0.05). Moreover, the effect of C. butyricum on TLR2 was positively correlated with IL17, IL23 and RORγt. CONCLUSIONS: C. butyricum exerts a dose-dependently protective effect on acute intestinal inflammation induced by DSS in mice, by inhibiting the TLR2 signaling pathway, down-regulating the expression of IL23 and RORγt, and inhibiting the secretion of IL17.


Assuntos
Clostridium butyricum , Colite/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Probióticos , Células Th17/imunologia , Receptor 2 Toll-Like/imunologia , Fator de Transcrição RelA/imunologia , Animais , Peso Corporal , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Comportamento de Ingestão de Líquido , Comportamento Alimentar , Feminino , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/genética , Interleucina-23/imunologia , Interleucina-23/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , RNA Mensageiro/metabolismo , Distribuição Aleatória , Transdução de Sinais , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo
13.
J Toxicol Sci ; 45(6): 327-337, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32493875

RESUMO

Hydrolyzed wheat proteins (HWPs) contained in cosmetics have occasionally caused immediate-type hypersensitivity following repeated skin exposure. Although the Cosmetic Ingredient Review Expert Panel concluded that < 3,500 Da HWP is safe for use in cosmetics, it remains biologically unknown how allergenic HWPs evoke immediate-type allergy percutaneously. Keratinocyte-derived thymic stromal lymphopoietin (TSLP) induces type 2 immune responses, which play an essential role in the pathogenesis of immediate-type allergy. Previously, we demonstrated that protein allergens in cultured human keratinocytes strongly induced long-form TSLP (loTSLP) transcription. However loTSLP-regulating signaling by HWP is poorly understood. In this study, we performed global gene expression analysis by microarray to investigate how the allergenic HWP acts on epidermal keratinocytes and the induction of loTSLP. Compared to human serum albumin (HSA), allergenic HWP induced a distinct gene expression pattern and preferentially activated various inflammatory pathways (High Mobility Group Box 1, Interleukin [IL]-6, IL-8, and acute phase response signaling). We identified 85 genes as potential nuclear factor-kappa B (NF-κB) target genes in GP19S-treated cells, compared with 29 such genes in HSA-treated cells. In addition, HWP specifically altered IL-17 signaling pathways in which transcription factors, NF-κB and activator protein-1, were activated. NF-κB signaling may be an important factor for HWP-induced inflammatory loTSLP transcription via inhibition assay. In conclusion, allergenic HWP caused an easily sensitizable milieu of activated inflammatory pathways and induced NF-κB-dependent loTSLP transcription in keratinocytes.


Assuntos
Citocinas , Queratinócitos/imunologia , NF-kappa B/metabolismo , Proteínas de Plantas/efeitos adversos , Transdução de Sinais , Transcrição Genética , Células Cultivadas , Citocinas/genética , Citocinas/fisiologia , Expressão Gênica , Humanos , Hidrólise , Hipersensibilidade Imediata/etiologia , Hipersensibilidade Imediata/genética , Inflamação/etiologia , Inflamação/genética , Interleucina-17/metabolismo , Queratinócitos/metabolismo , Triticum
14.
Nat Commun ; 11(1): 2099, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350248

RESUMO

Besides pro-inflammatory roles, the ancient cytokine interleukin-17 (IL-17) modulates neural circuit function. We investigate IL-17 signaling in neurons, and the extent it can alter organismal phenotypes. We combine immunoprecipitation and mass spectrometry to biochemically characterize endogenous signaling complexes that function downstream of IL-17 receptors in C. elegans neurons. We identify the paracaspase MALT-1 as a critical output of the pathway. MALT1 mediates signaling from many immune receptors in mammals, but was not previously implicated in IL-17 signaling or nervous system function. C. elegans MALT-1 forms a complex with homologs of Act1 and IRAK and appears to function both as a scaffold and a protease. MALT-1 is expressed broadly in the C. elegans nervous system, and neuronal IL-17-MALT-1 signaling regulates multiple phenotypes, including escape behavior, associative learning, immunity and longevity. Our data suggest MALT1 has an ancient role modulating neural circuit function downstream of IL-17 to remodel physiology and behavior.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/imunologia , Caenorhabditis elegans/fisiologia , Imunidade , Interleucina-17/metabolismo , Longevidade , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Neurônios/metabolismo , Animais , Comportamento Animal , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Imunidade/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Longevidade/efeitos dos fármacos , Modelos Biológicos , Neurônios/efeitos dos fármacos , Oxigênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Frações Subcelulares/metabolismo , Transgenes
16.
Am J Pathol ; 190(8): 1701-1712, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32416098

RESUMO

Interleukin 17A (IL-17A) is critical in the pathogenesis of autoimmune diseases through driving inflammatory cascades. However, the role of IL-17 in osteoarthritis (OA) is not well understood. Tumor necrosis factor-receptor-associated factor 3 (TRAF3) is a receptor proximal negative regulator of IL-17 signaling. It remains unclear whether TRAF3 exerts regulatory effects on cartilage degradation and contributes to the pathogenesis of OA. In this study, we found that TRAF3 notably suppressed IL-17-induced NF-κB and mitogen-activated protein kinase activation and, subsequently, the production of matrix-degrading enzymes. TRAF3 depletion enhanced IL-17 signaling, along with increased matrix-degrading enzyme production. In vivo, cartilage destruction caused by surgery-induced OA was alleviated markedly both in 1l17a-deficient mice and in TRAF3 transgenic mice. In contrast, silencing TRAF3 through adenoviruses worsened cartilage degradation in experimental OA. Moreover, the destructive effect of IL-17 on cartilage was abolished in TRAF3 transgenic mice in an IL-17 intra-articular injection animal model. Similarly, genetic deletion of IL-17 blocked TRAF3 knockdown-mediated promotion of cartilage destruction, suggesting that the protective effect of TRAF3 on cartilage is mediated by its suppression of IL-17 signaling. Collectively, our results suggest that TRAF3 negatively regulates IL-17-mediated cartilage degradation and pathogenesis of OA, and may serve as a potential new therapy target for OA.


Assuntos
Artrite Experimental/metabolismo , Cartilagem Articular/metabolismo , Interleucina-17/metabolismo , Osteoartrite/metabolismo , Transdução de Sinais/fisiologia , Fator 3 Associado a Receptor de TNF/metabolismo , Animais , Artrite Experimental/genética , Artrite Experimental/patologia , Cartilagem Articular/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Osteoartrite/genética , Osteoartrite/patologia , Fator 3 Associado a Receptor de TNF/genética
17.
Nat Commun ; 11(1): 2608, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32451418

RESUMO

IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-ß1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-ß signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-ß1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-ß signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-ß signaling. We show that TGF-ß, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.


Assuntos
Colite/complicações , Neoplasias do Colo/etiologia , Interleucinas/biossíntese , Células Th17/imunologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/imunologia , Diferenciação Celular , Colite/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/imunologia , Células Th17/patologia , Fator de Crescimento Transformador beta1/metabolismo
18.
Am J Physiol Cell Physiol ; 319(2): C331-C344, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432926

RESUMO

The pH of airway surface liquid (ASL) is a key factor that determines respiratory host defense; ASL acidification impairs and alkalinization enhances key defense mechanisms. Under healthy conditions, airway epithelia secrete base ([Formula: see text]) and acid (H+) to control ASL pH (pHASL). Neutrophil-predominant inflammation is a hallmark of several airway diseases, and TNFα and IL-17 are key drivers. However, how these cytokines perturb pHASL regulation is uncertain. In primary cultures of differentiated human airway epithelia, TNFα decreased and IL-17 did not change pHASL. However, the combination (TNFα+IL-17) markedly increased pHASL by increasing [Formula: see text] secretion. TNFα+IL-17 increased expression and function of two apical [Formula: see text] transporters, CFTR anion channels and pendrin Cl-/[Formula: see text] exchangers. Both were required for maximal alkalinization. TNFα+IL-17 induced pendrin expression primarily in secretory cells where it was coexpressed with CFTR. Interestingly, significant pendrin expression was not detected in CFTR-rich ionocytes. These results indicate that TNFα+IL-17 stimulate [Formula: see text] secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Interleucina-17/genética , Mucosa Respiratória/metabolismo , Transportadores de Sulfato/genética , Fator de Necrose Tumoral alfa/genética , Álcalis/metabolismo , Bicarbonatos/metabolismo , Antiportadores de Cloreto-Bicarbonato/metabolismo , Citocinas/genética , Citocinas/metabolismo , Células Epiteliais/metabolismo , Humanos , Interleucina-17/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
PLoS One ; 15(4): e0222969, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32352958

RESUMO

In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A is a pro-inflammatory cytokine mainly secreted by T helper-17 cells that is critically involved in psoriasis pathogenesis. IL-36α, IL-36ß and IL-36γ are also inflammatory cytokines up-regulated in psoriasis and induced by various stimuli, including IL-17A. In this study, we found that human keratinocytes are the main source of IL-36, in particular of IL-36γ. This cytokine was strongly induced by IL-17A and, together with IL-17A, efficiently activated human dermal microvascular endothelial cells (HDMECs), which expressed both IL-17 and IL-36 receptors. Both IL-36γ and IL-17A induced cell proliferation through specific molecular cascades involving ERK1/2 only or ERK1/2, STAT3 and NF-κB, respectively. We highlighted the intense IL-17A- and IL-36γ -dependent interplay between keratinocytes and HDMECs, likely active in the psoriatic lesions and leading to the establishment of a cytokine network responsible for the development and maintenance of the inflamed state. IL-17A or IL-36γ showed in HDMECs a synergic activity with TNF-α by potently inducing inflammatory cytokine/chemokine release and ICAM-1 expression. We also investigated the involvement of IL-36γ and VEGF-A, substantially reduced in lesional skin of psoriatic patients pharmacologically treated with the anti-IL-17A antibody Secukinumab. Importantly, keratinocyte-derived IL-36γ represented an additional pro-angiogenic mediator of IL-17A. We observed that keratinocyte-derived VEGF-A influenced proliferation but did not act on expression of adhesion molecules in HDMECs. On the other hand, inhibition of IL-36γ released by IL-17A-treated keratinocytes impaired either proliferation or ICAM-1 expression both in HDMECs and in an in vivo murine model of psoriasis. Taken together, our data demonstrated that IL-17A and IL-36γ are highly involved in endothelial cells/keratinocytes crosstalk in inflammatory skin conditions.


Assuntos
Comunicação Celular , Células Endoteliais/metabolismo , Interleucina-17/metabolismo , Interleucina-1/metabolismo , Queratinócitos/metabolismo , Psoríase/metabolismo , Células Cultivadas , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
PLoS One ; 15(4): e0231222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32251446

RESUMO

IL-17A and IL-17F cytokines are important regulators of acute graft-versus-host-disease (GVHD). However, contrary effects of these cytokines in inflammatory diseases have been reported. To investigate the effects of donor-derived IL-17A and IL-17F on GVHD, we made use of single (Il17a-/- or Il17f-/-) and double deficient (Il17af-/-) allogeneic donor CD4+ T cells. We could demonstrate that transplantation of Il17af-/- CD4+ donor T cells led to aggravated GVHD. However, this phenotype was not observed after transplantation of single, Il17a-/- or Il17f-/-, deficient CD4+ T cells, suggesting redundant effects of IL-17A and IL-17F. Moreover, Il17af-/- cell recipients showed an increase of systemic IFNγ, indicating a heightened pro-inflammatory state, as well as infiltration of IFNγ-secreting CD4+ T cells in the recipients' intestinal tract. These recipients exhibited significant gut leakage, and markedly macrophage infiltration in the gastrointestinal epithelial layer. Moreover, we saw evidence of impaired recovery of gut epithelial cells in recipients of Il17af-/- CD4+ T cells. In this study, we show that IL-17A/F double deficiency of donor CD4+ T cells leads to accelerated GVHD and therefore highlight the importance of these cytokines. Together, IL-17 cytokines might serve as a brake to an intensified Th1 response, leading to the exacerbated gut damage in acute GVHD.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Interleucina-17/metabolismo , Intestinos/imunologia , Células Th1/citologia , Animais , Transplante de Medula Óssea , Linfócitos T CD4-Positivos/citologia , Células CACO-2 , Proliferação de Células , Microbioma Gastrointestinal , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , RNA Ribossômico 16S/metabolismo
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