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1.
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
2.
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
3.
Front Immunol ; 11: 1311, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32676080

RESUMO

Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.


Assuntos
Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Interferon gama/genética , Interleucina-17/genética , Inibidores de Janus Quinases/uso terapêutico , Pneumonia Viral/patologia , Pirazóis/uso terapêutico , Animais , Células Cultivadas , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/prevenção & controle , Citocinas/sangue , Citocinas/imunologia , Antígeno HLA-DR3/genética , Intestino Delgado/imunologia , Intestino Delgado/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Knockout , Pandemias , Pneumonia Viral/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/imunologia
4.
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
5.
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
8.
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
9.
Clin Exp Rheumatol ; 38 Suppl 124(2): 166-170, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32242803

RESUMO

OBJECTIVES: Cytokines signaling pathway genes represent a key component of the genetic network implicated in the pathogenesis of immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. Interleukin (IL)17A is described as a genetic risk locus for some autoimmune diseases, such as giant cell arteritis and spondyloarthritis. Accordingly, we aimed to determine the potential influence of IL17A on the pathogenesis of IgAV. METHODS: Five IL17A tag polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909), which cover the major variability of this gene, were genotyped in 360 Caucasian patients with IgAV and 1,003 sex and ethnically matched healthy controls using TaqMan probes. RESULTS: No statistically significant differences between patients with IgAV and healthy controls were observed when each IL17A genetic variant was analysed independently. Similarly, no statistically significant differences between patients with IgAV and healthy controls were found when the five IL17A polymorphisms were evaluated combined conforming haplotypes. In addition, there were no statistically significant differences in genotype, allele and haplotype frequencies of IL17A when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IL17A on the pathogenesis of IgAV.


Assuntos
Predisposição Genética para Doença , Imunoglobulina A , Interleucina-17/genética , Vasculite/genética , Estudos de Casos e Controles , Redes Reguladoras de Genes , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , Vasculite/patologia
10.
Immunity ; 52(3): 528-541.e7, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32160525

RESUMO

Helminths, allergens, and certain protists induce type 2 immune responses, but the underlying mechanisms of immune activation remain poorly understood. In the small intestine, chemosensing by epithelial tuft cells results in the activation of group 2 innate lymphoid cells (ILC2s), which subsequently drive increased tuft cell frequency. This feedforward circuit is essential for intestinal remodeling and helminth clearance. ILC2 activation requires tuft-cell-derived interleukin-25 (IL-25), but whether additional signals regulate the circuit is unclear. Here, we show that tuft cells secrete cysteinyl leukotrienes (cysLTs) to rapidly activate type 2 immunity following chemosensing of helminth infection. CysLTs cooperate with IL-25 to activate ILC2s, and tuft-cell-specific ablation of leukotriene synthesis attenuates type 2 immunity and delays helminth clearance. Conversely, cysLTs are dispensable for the tuft cell response induced by intestinal protists. Our findings identify an additional tuft cell effector function and suggest context-specific regulation of tuft-ILC2 circuits within the small intestine.


Assuntos
Cisteína/imunologia , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Leucotrienos/imunologia , Nippostrongylus/imunologia , Infecções por Strongylida/imunologia , Animais , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/imunologia , Araquidonato 5-Lipoxigenase/metabolismo , Cisteína/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/parasitologia , Imunidade Inata/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitologia , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Leucotrienos/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/parasitologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nippostrongylus/fisiologia , Infecções por Strongylida/parasitologia
12.
Life Sci ; 248: 117456, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32097666

RESUMO

AIMS: In this study, we will investigate the therapeutic effects of berberine (BBR) in Helicobacter pylori (H. pylori) induced chronic atrophic gastritis (CAG). Furthermore, potential mechanisms of BBR in regulating IRF8-IFN-γ signaling axis will also be investigated. MATERIALS AND METHODS: H. pylori were utilized to establish CAG model of rats. Therapeutic effects of BBR on serum supernatant indices, and histopathology of stomach were analyzed in vivo. Moreover, GES-1 cells were infected by H. pylori, and intervened with BBR in vitro. Cell viability, morphology, proliferation, and quantitative analysis were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression in IRF8-IFN-γ signaling axis were measured. KEY FINDINGS: Results showed serum supernatant indices including IL-17, CXCL1, and CXCL9 were downregulated by BBR intervention, while, G-17 increased significantly. Histological injuries of gastric mucosa induced by H. pylori also were alleviated. Moreover, cell viability and morphology changes of GES-1 cells were improved by BBR intervention. In addition, proinflammatory genes and IRF8-IFN-γ signaling axis related genes, including Ifit3, Upp1, USP18, Nlrc5, were suppressed by BBR administration in vitro and in vivo. The proteins expression related to IRF8-IFN-γ signaling axis, including Ifit3, IRF1 and Ifit1 were downregulated by BBR intervention.


Assuntos
Anti-Inflamatórios/farmacologia , Berberina/farmacologia , Gastrite Atrófica/tratamento farmacológico , Infecções por Helicobacter/tratamento farmacológico , Fatores Reguladores de Interferon/genética , Interferon gama/genética , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL1/antagonistas & inibidores , Quimiocina CXCL1/genética , Quimiocina CXCL1/imunologia , Quimiocina CXCL9/antagonistas & inibidores , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Doença Crônica , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Gastrite Atrófica/genética , Gastrite Atrófica/imunologia , Gastrite Atrófica/microbiologia , Regulação da Expressão Gênica , Infecções por Helicobacter/genética , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/crescimento & desenvolvimento , Helicobacter pylori/patogenicidade , Humanos , Fatores Reguladores de Interferon/antagonistas & inibidores , Fatores Reguladores de Interferon/imunologia , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Interleucina-17/agonistas , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Proteínas NLR/antagonistas & inibidores , Proteínas NLR/genética , Proteínas NLR/imunologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Uridina Fosforilase/antagonistas & inibidores , Uridina Fosforilase/genética , Uridina Fosforilase/imunologia
13.
Parasite Immunol ; 42(5): e12703, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32043596

RESUMO

Excretory/secretory proteins of Haemonchus contortus (HcESPs) intermingle comprehensively with host immune cells and modulate host immune responses. In this study, H contortus ES antigen named as elongation factor 1 alpha (HcEF-1α) was cloned and expressed. The influences of recombinant HcEF-1α on multiple functions of goat peripheral blood mononuclear cells (PBMCs) were observed in vitro. Immunoblot analysis revealed that rHcEF-1α was recognized by the serum of goat infected with H contortus. Immunofluorescence analysis indicated that rHcEF-1α was bound on surface of PBMCs. Moreover, the productions of IL-4, TGF-ß1, IFN-γ and IL-17 of cells were significantly modulated by the incubation with rHcEF-1α. The production of interleukin IL-10 was decreased. Cell migration, cell proliferation and cell apoptosis were significantly increased; however, nitric oxide production (NO) was significantly decreased. The MHC II molecule expression of cells incubated with rHcEF-1α was increased significantly, whereas MHC-I was not changed as compared to the control groups (PBS control and pET32a). These findings indicated that rHcEF-1α protein might play essential roles in functional regulations of HcESPs on goat PBMC and mediate the immune responses of the host during host-parasite relationship.


Assuntos
Doenças das Cabras/parasitologia , Hemoncose/veterinária , Haemonchus/imunologia , Proteínas de Helminto/imunologia , Leucócitos Mononucleares/imunologia , Fator 1 de Elongação de Peptídeos/imunologia , Animais , Apoptose , Movimento Celular , Proliferação de Células , Doenças das Cabras/genética , Doenças das Cabras/imunologia , Doenças das Cabras/fisiopatologia , Cabras , Hemoncose/imunologia , Hemoncose/parasitologia , Hemoncose/fisiopatologia , Haemonchus/genética , Proteínas de Helminto/genética , Interleucina-17/genética , Interleucina-17/imunologia , Óxido Nítrico/imunologia , Fator 1 de Elongação de Peptídeos/genética
14.
Nature ; 578(7796): 610-614, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32076265

RESUMO

The sympathetic nervous system innervates peripheral organs to regulate their function and maintain homeostasis, whereas target cells also produce neurotrophic factors to promote sympathetic innervation1,2. The molecular basis of this bi-directional communication remains to be fully determined. Here we use thermogenic adipose tissue from mice as a model system to show that T cells, specifically γδ T cells, have a crucial role in promoting sympathetic innervation, at least in part by driving the expression of TGFß1 in parenchymal cells via the IL-17 receptor C (IL-17RC). Ablation of IL-17RC specifically in adipose tissue reduces expression of TGFß1 in adipocytes, impairs local sympathetic innervation and causes obesity and other metabolic phenotypes that are consistent with defective thermogenesis; innervation can be fully rescued by restoring TGFß1 expression. Ablating γδ Τ cells and the IL-17RC signalling pathway also impairs sympathetic innervation in other tissues such as salivary glands. These findings demonstrate coordination between T cells and parenchymal cells to regulate sympathetic innervation.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/inervação , Tecido Adiposo/metabolismo , Interleucina-17/metabolismo , Sistema Nervoso Simpático/fisiologia , Linfócitos T/metabolismo , Termogênese , Tecido Adiposo Marrom/metabolismo , Animais , Interleucina-17/deficiência , Interleucina-17/genética , Masculino , Camundongos , Camundongos Knockout , Especificidade de Órgãos , Tecido Parenquimatoso/citologia , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
15.
Nat Commun ; 11(1): 900, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060280

RESUMO

Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis.


Assuntos
Colo/imunologia , Neoplasias do Colo/imunologia , Cobre/metabolismo , Proteínas Inibidoras de Apoptose/imunologia , Interleucina-17/imunologia , Proteínas de Membrana/imunologia , Animais , Carcinogênese , Colite/genética , Colite/imunologia , Colite/metabolismo , Colo/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Cobre/imunologia , Humanos , Proteínas Inibidoras de Apoptose/genética , Interleucina-17/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
16.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(2): 141-145, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32051081

RESUMO

OBJECTIVE: To study the association of single nucleotide polymorphisms (SNPs) of interleukin-23 receptor (IL-23R) rs10889677, interleukin-17A (IL-17A) rs227591, and interleukin-17F (IL-17F) rs763780 with necrotizing enterocolitis (NEC) in Chinese Han preterm infants. METHODS: A total of 100 Chinese Han preterm infants with NEC who were admitted to the neonatal intensive care unit from January 2017 to January 2019 were prospectively enrolled. Of the 100 preterm infants, 63 had stage II NEC and 37 had stage III NEC. A total of 100 preterm infants, matched for age and sex, were selected as the control group. PCR and Sanger sequencing were used to determine the SNPs of rs10889677, rs2275913, and rs763780. An unconditional logistic regression analysis was used to investigate the association of SNPs with NEC susceptibility and severity. RESULTS: The genotype and allele frequencies of rs10889677 and rs2275913 had no influence on the development of NEC (P>0.05). The genotype of rs763780 had no influence on the development of NEC (P>0.05), but the risk of NEC in the infants carrying C allele was 1.652 times that in those carrying T allele (95%CI: 1.052-2.695, P<0.05). The risk of NEC in the infants carrying TC+CC genotype was 1.856 times that in those carrying TT genotype (95%CI: 1.045-3.201, P<0.05). The risk of stage III NEC in the infants carrying TC+CC genotype was 2.965 times that in those carrying TT genotype (95%CI: 1.052-6.330, P<0.05). The risk of stage III NEC in the infants carrying C allele was 2.363 times that in those carrying T allele (95%CI: 1.034-4.093, P<0.05). CONCLUSIONS: The SNPs of IL-23R rs10889677 and IL-17A rs2275913 are not associated with the susceptibility to NEC in Chinese Han preterm infants, while TC+CC genotype and C allele of IL-17F rs763780 are associated with the susceptibility to NEC and the severity of NEC.


Assuntos
Enterocolite Necrosante , Interleucina-17/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Enterocolite Necrosante/genética , Predisposição Genética para Doença , Genótipo , Humanos , Recém-Nascido , Recém-Nascido Prematuro
17.
PLoS One ; 15(1): e0227993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990927

RESUMO

OBJECTIVES: The regulatory mechanisms affecting the modulation of the immune system accompanying the progressive effort to exhaustion, particularly associated with T cells, are not fully understood. We analysed the impact of two progressive effort protocols on T helper (Th) cell distribution and selected cytokines. METHODS: Sixty-two male soccer players with a median age of 17 (16-29) years performed different protocols for progressive exercise until exhaustion: YO-YO (YYRL1) and Beep. Blood samples for all analyses were taken three times: at baseline, post-effort, and in recovery. RESULTS: The percentage of Th1 cells increased post-effort and in recovery. The post-effort percentage of Th1 cells was higher in the Beep group compared to the YYRL1 group. Significant post-effort increase in Th17 cells was observed in both groups. The post-effort percentage of regulatory T cells (Treg) increased in the Beep group. An increased post-effort concentration of IL-2, IL-6, IL-8 and IFN-γ in both groups was observed. Post-effort TNF-α and IL-10 levels were higher than baseline in the YYRL1 group, while the post-effort IL-17A concentration was lower than baseline only in the Beep group. The recovery IL-2, IL-4, TNF-α and IFN-γ levels were higher than baseline in the YYRL1 group. The recovery IL-4, IL-6, IL-8, TNF-α and IFN-γ values were higher than baseline in the Beep group. CONCLUSION: The molecular patterns related to cytokine secretion are not the same between different protocols for progressive effort. It seems that Treg cells are probably the key cells responsible for silencing the inflammation and enhancing anti-inflammatory pathways.


Assuntos
Esforço Físico/imunologia , Futebol/fisiologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adolescente , Adulto , Atletas , Expressão Gênica/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Masculino , Esforço Físico/genética , Recuperação de Função Fisiológica/imunologia , Linfócitos T Reguladores/citologia , Células Th1/citologia , Células Th17/citologia , Células Th2/citologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
18.
Immunology ; 159(4): 404-412, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31909831

RESUMO

Dendritic cells (DCs) are potent immune cells that control innate and adaptive immune responses. Previous studies have shown that the DCs are required for protection against Staphylococcus aureus infection. However, the role of conventional DC (cDC) subsets during S. aureus infection in vivo has not been well investigated. In this study, we examined the function of spleen DC subsets in the activation of immunity against S. aureus infection. C57BL/6 mice were infected intravenously with S. aureus and DC and T-cell activation were analyzed in vivo. We found that the spleen CD8α- cDCs phagocytosed S. aureus more efficiently than type-1 conventional DCs (cDC1s) did. Moreover, the CD8α- cDCs contributed to the production of pro-inflammatory cytokines in response to S. aureus infection, whereas the cDC1s did not. In addition, infection with S. aureus promoted an increase in the number of Vß T cells. The CD4+ and CD8+ Vß T cells up-regulated the production of interferon-γ (IFN-γ) and interleukin-17 (IL-17) in response to S. aureus infection. Importantly, the induction of IFN-γ and IL-17 production in CD4+ and CD8+ Vß T cells was mediated by S. aureus-stimulated CD8α- cDCs, whereas cDC1s failed to promote IFN-γ and IL-17 production in the cells. Therefore, these data suggested that the spleen CD8α- cDCs are the main DC subsets for induction of S. aureus superantigen-specific immunity.


Assuntos
Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD4-Positivos/patologia , Antígenos CD8/deficiência , Antígenos CD8/genética , Linfócitos T CD8-Positivos/microbiologia , Linfócitos T CD8-Positivos/patologia , Linhagem da Célula/imunologia , Células Dendríticas/microbiologia , Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Imunidade Celular , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Baço/imunologia , Baço/microbiologia , Baço/patologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus/patogenicidade
19.
Cancer Immunol Immunother ; 69(1): 115-126, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31802182

RESUMO

Pro-inflammatory cytokines are crucial mediators of cancer development, representing potential targets for cancer therapy. The molecular mechanism of a vital pro-inflammatory cytokine, IL-17A, in cancer progression and its potential use in therapy through influencing fatty acid (FA) metabolism, especially FA uptake of cancer cells, remains unknown. In the present study, we used IL-17A and ovarian cancer (OvCa), a representative of both obesity-related and inflammation-related cancers, to explore the interactions among IL-17A, cancer cells and adipocytes (which can provide FAs). We found that in the presence of palmitic acid (PA), IL-17A could directly increase the cellular uptake of PA, leading to the proliferation of OvCa cells via the IL-17A/IL-17RA/p-STAT3/FABP4 axis rather than via CD36. Moreover, in vivo experiments using an orthotopic implantation model in IL-17A-deficient mice demonstrated that endogenous IL-17A could fuel OvCa growth and metastasis with increased expression of FABP4 and p-STAT3. Furthermore, analysis of clinical specimens supported the above findings. Our data not only provide useful insights into the clinical intervention of the growth and metastasis of the tumors (such as OvCa) that are prone to growth and metastasis in an adipocyte-rich microenvironment (ARM) but also provides new insights into the roles of IL-17A in tumor progression and immunomodulatory therapy of OvCa.


Assuntos
Adipócitos/imunologia , Interleucina-17/metabolismo , Neoplasias Ovarianas/imunologia , Ácido Palmítico/metabolismo , Adipócitos/metabolismo , Animais , Antígenos CD36/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Ovário/patologia , Fosforilação , Receptores de Interleucina-17/metabolismo , Proteínas Recombinantes/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Microambiente Tumoral/imunologia
20.
Am J Physiol Renal Physiol ; 318(1): F238-F247, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760767

RESUMO

Toll-like receptor 9 (TLR9), which is activated by endogenously released mtDNA during sepsis, contributes to the development of polymicrobial septic acute kidney injury (AKI). However, downstream factors of TLR9 to AKI remain unknown. We hypothesized that IL-17A activated by TLR9 may play a critical role in septic AKI development. To determine the effects of TLR9 on IL-17A production in septic AKI, we used a cecal ligation and puncture (CLP) model in Tlr9 knockout (Tlr9KO) mice and wild-type (WT) littermates. We also investigated the pathway from TLR9 activation in dendritic cells (DCs) to IL-17A production by γδT cells in vitro. To elucidate the effects of IL-17A on septic AKI, Il-17a knockout (Il-17aKO) mice and WT littermates were subjected to CLP. We further investigated the relationship between the TLR9-IL-17A axis and septic AKI by intravenously administering recombinant IL-17A or vehicle into Tlr9KO mice and assessing kidney function. IL-17A levels in both plasma and the peritoneal cavity and mRNA levels of IL-23 in the spleen were significantly higher in WT mice after CLP than in Tlr9KO mice. Bone marrow-derived DCs activated by TLR9 induced IL-23 and consequently promoted IL-17A production in γδT cells in vitro. Knockout of Il-17a improved survival, functional and morphological aspects of AKI, and splenic apoptosis after CLP. Exogenous IL-17A administration aggravated CLP-induced AKI attenuated by knockout of Tlr9. TLR9 in DCs mediated IL-17A production in γδT cells during sepsis and contributed to the development of septic AKI.


Assuntos
Lesão Renal Aguda/metabolismo , Interleucina-17/metabolismo , Sepse/metabolismo , Receptor Toll-Like 9/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose , Citocinas/metabolismo , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Interleucina-17/genética , Interleucina-17/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos , Camundongos Knockout , Sepse/patologia , Baço/metabolismo , Receptor Toll-Like 9/genética
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