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1.
Nutrients ; 13(6)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207960

RESUMO

Psoriasis is an immune-mediated systemic disease that may be treated with probiotics. In this study, probiotic strains that could or could not decrease interleukin (IL)-17 levels were applied to imiquimod (IMQ)-induced psoriasis-like mice via oral administration. Bifidobacteriumadolescentis CCFM667, B. breve CCFM1078, Lacticaseibacillusparacasei CCFM1074, and Limosilactobacillus reuteri CCFM1132 ameliorated psoriasis-like pathological characteristics and suppressed the release of IL-23/T helper cell 17 (Th17) axis-related inflammatory cytokines, whereas B. animalis CCFM1148, L. paracasei CCFM1147, and L. reuteri CCFM1040 neither alleviated the pathological characteristics nor reduced the levels of inflammatory cytokines. All effective strains increased the contents of short-chain fatty acids, which were negatively correlated with the levels of inflammatory cytokines. By performing 16S rRNA gene sequencing, the diversity of gut microbiota in psoriasis-like mice was found to decrease, but all effective strains made some specific changes to the composition of gut microbiota compared to the ineffective strains. Furthermore, except for B. breve CCFM1078, all other effective strains decreased the abundance of the family Rikenellaceae, which was positively correlated with psoriasis-like pathological characteristics and was negatively correlated with propionate levels. These findings demonstrated effects of strain-specificity, and how probiotics ameliorated psoriasis and provide new possibilities for the treatment of psoriasis.


Assuntos
Microbioma Gastrointestinal , Probióticos/uso terapêutico , Psoríase/dietoterapia , Psoríase/microbiologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bifidobacterium/fisiologia , Citocinas/imunologia , Citocinas/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Feminino , Imiquimode , Interleucinas/análise , Interleucinas/metabolismo , Lactobacillaceae/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Probióticos/farmacologia , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Células Th17/imunologia
2.
Cell Prolif ; 54(7): e13075, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34101283

RESUMO

OBJECTIVES: Oestrogen deficiency is an aetiological factor of postmenopausal osteoporosis (PMO), which not only decreases bone density in vertebrae and long bone but also aggravates inflammatory alveolar bone loss. Recent evidence has suggested the critical role of gut microbiota in osteoimmunology and its influence on bone metabolisms. The present study aimed to evaluate the therapeutic effects of probiotics on alveolar bone loss under oestrogen-deficient condition. MATERIALS AND METHODS: Inflammatory alveolar bone loss was established in ovariectomized (OVX) rats, and rats were daily intragastrically administered with probiotics until sacrifice. Gut microbiota composition, intestinal permeability, systemic immune status and alveolar bone loss were assessed to reveal the underlying correlation between gut microbiota and bone metabolisms. RESULTS: We found administration of probiotics significantly prevented inflammatory alveolar bone resorption in OVX rats. By enriching butyrate-producing genera and enhancing gut butyrate production, probiotics improved intestinal barrier and decreased gut permeability in the OVX rats. Furthermore, the oestrogen deprivation-induced inflammatory responses were suppressed in probiotics-treated OVX rats, as reflected by reduced serum levels of inflammatory cytokines and a balanced distribution of CD4+ IL-17A+ Th17 cells and CD4+ CD25+ Foxp3+ Treg cells in the bone marrow. CONCLUSIONS: This study demonstrated that probiotics can effectively attenuate alveolar bone loss by modulating gut microbiota and further regulating osteoimmune response and thus represent a promising adjuvant in the treatment of alveolar bone loss under oestrogen deficiency.


Assuntos
Perda do Osso Alveolar/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Probióticos/farmacologia , Perda do Osso Alveolar/metabolismo , Animais , Citocinas/sangue , Regulação para Baixo/efeitos dos fármacos , Fezes/química , Feminino , Fêmur/diagnóstico por imagem , Mandíbula/diagnóstico por imagem , Mandíbula/patologia , Ovariectomia , Ratos , Ratos Sprague-Dawley , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo , Microtomografia por Raio-X
3.
Front Immunol ; 12: 620916, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140947

RESUMO

Background: Previous studies reported that various miRNAs participate in autoimmune diseases, but the potential regulatory mechanism of miRNAs in autoimmune thyroiditis (AIT) needs further exploration. Objective: This study aimed to further verify that miR-326 contributes to AIT by regulating Th17/Treg balance through Ets-1 using lentiviral gene delivery through tail vein and thyroid injection in NOD.H-2h4 mice. Materials and Methods: Five-week-old NOD.H-2h4 mice were divided randomly into tail vein and thyroid injection groups, and each received either mmu-miR-326 sponge (LV-sponge) or lentiviral vector control. Mice were divided for tail vein injection: the therapeutic LV-ctrl, therapeutic LV-sponge, prophylactic LV-ctrl, and prophylactic LV-sponge groups. The control group was fed high-iodine water without vein injection. The thyroid infiltration of lymphocytes and serum TgAb value were investigated by thyroid hematoxylin and eosin (HE) staining and ELISA, respectively. Ets-1 and lymphocyte counts were measured by RT-PCR, western blotting, and flow cytometry. The thyroid CD4+IL-17a+ cells and CD4+Ets-1+ cells were detected by immunofluorescence, and the serum cytokines were tested by ELISA. Results: In the tail vein injection groups, the thyroid inflammatory score and serum TgAb titer were significantly lower in the LV-sponge groups than in the control and LV-ctrl groups while Ets-1 protein expression in mouse spleens was increased in the LV-sponge groups. Moreover, Th17/Treg ratio declined in the LV-sponge group and decreased significantly in the prophylactic LV-sponge group (P = 0.036) tested by flow cytometry. Immunofluorescence showed that, in LV-sponge groups, CD4+IL-17a+ cells were decreased significantly (P = 0.001), while CD4+Ets-1+ cells were increased significantly in the LV-sponge group (P = 0.029). The serum IL-17/IL-10 was decreased significantly in the LV-sponge group (P < 0.05). In the thyroid injection groups, the thyroid inflammatory score and serum TgAb titer in the LV-sponge group decreased significantly compared with those in the LV-ctrl group (P < 0.05). In addition, in LV-sponge groups, CD4+IL-17a+ cells were decreased, while CD4+Ets-1+ cells were increased significantly in the inhibition group evaluated by immunofluorescence. Moreover, tail vein injection of LV-sponge resulted in much lower TgAb levels in thyroiditis compared with thyroid injection. Conclusion: MiR-326 targeted therapy may be a promising approach for AIT. In addition, tail vein injection may achieve a better intervention effect than thyroid injection.


Assuntos
MicroRNAs/genética , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Tireoidite Autoimune/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos NOD , Proteína Proto-Oncogênica c-ets-1/genética , Proteína Proto-Oncogênica c-ets-1/metabolismo
4.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073458

RESUMO

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell-cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.


Assuntos
Doenças Autoimunes/imunologia , Proliferação de Células , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Antígeno CTLA-4/imunologia , Feminino , Granzimas/imunologia , Humanos , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Linfócitos T Reguladores/citologia , Células Th17/citologia
5.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070011

RESUMO

Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.


Assuntos
Dopamina/imunologia , Esclerose Múltipla/tratamento farmacológico , Receptores Dopaminérgicos/efeitos dos fármacos , Animais , Dopamina/fisiologia , Dopaminérgicos/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/fisiopatologia , Humanos , Camundongos , Modelos Imunológicos , Modelos Neurológicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/fisiopatologia , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologia , Receptores Dopaminérgicos/imunologia , Receptores Dopaminérgicos/fisiologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
6.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071562

RESUMO

The skin is the outermost layer of the body and is exposed to many environmental stimuli, which cause various inflammatory immune responses in the skin. Among them, fungi are common microorganisms that colonize the skin and cause cutaneous fungal diseases such as candidiasis and dermatophytosis. The skin exerts inflammatory responses to eliminate these fungi through the cooperation of skin-component immune cells. IL-17 producing cells are representative immune cells that play a vital role in anti-fungal action in the skin by producing antimicrobial peptides and facilitating neutrophil infiltration. However, the actual impact of IL-17-producing cells in cutaneous fungal infections remains unclear. In this review, we focused on the role of IL-17-producing cells in a series of cutaneous fungal infections, the characteristics of skin infectious fungi, and the recognition of cell components that drive cutaneous immune cells.


Assuntos
Candidíase/imunologia , Fungos/imunologia , Interleucina-17/imunologia , Pele/imunologia , Células Th17/imunologia , Tinha/imunologia , Animais , Candidíase/microbiologia , Fungos/fisiologia , Humanos , Interleucina-17/metabolismo , Infiltração de Neutrófilos/imunologia , Proteínas Citotóxicas Formadoras de Poros/imunologia , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Pele/microbiologia , Células Th17/metabolismo , Tinha/microbiologia
8.
Front Immunol ; 12: 593473, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968012

RESUMO

T helper 17 (Th17) cells are characterized by the secretion of the IL-17 cytokine and are essential for the immune response against bacterial and fungal infections. Despite the beneficial roles of Th17 cells, unrestrained IL-17 production can contribute to immunopathology and inflammatory autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Although these diverse outcomes are directed by the activation of Th17 cells, the regulation of Th17 cells is incompletely understood. The discovery that microRNAs (miRNAs) are involved in the regulation of Th17 cell differentiation and function has greatly improved our understanding of Th17 cells in immune response and disease. Here, we provide an overview of the biogenesis and function of miRNA and summarize the role of miRNAs in Th17 cell differentiation and function. Finally, we focus on recent advances in miRNA-mediated dysregulation of Th17 cell fate in autoimmune diseases.


Assuntos
Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Autoimunidade/genética , Suscetibilidade a Doenças , MicroRNAs/genética , Células Th17/imunologia , Células Th17/metabolismo , Animais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/terapia , Biomarcadores , Gerenciamento Clínico , Regulação da Expressão Gênica , Humanos , Interferência de RNA
9.
EMBO Mol Med ; 13(6): e14045, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33961735

RESUMO

The immune responses and mechanisms limiting symptom progression in asymptomatic cases of SARS-CoV-2 infection remain unclear. We comprehensively characterized transcriptomic profiles, cytokine responses, neutralization capacity of antibodies, and cellular immune phenotypes of asymptomatic patients with acute SARS-CoV-2 infection to identify potential protective mechanisms. Compared to symptomatic patients, asymptomatic patients had higher counts of mature neutrophils and lower proportion of CD169+ expressing monocytes in the peripheral blood. Systemic levels of pro-inflammatory cytokines were also lower in asymptomatic patients, accompanied by milder pro-inflammatory gene signatures. Mechanistically, a more robust systemic Th2 cell signature with a higher level of virus-specific Th17 cells and a weaker yet sufficient neutralizing antibody profile against SARS-CoV-2 was observed in asymptomatic patients. In addition, asymptomatic COVID-19 patients had higher systemic levels of growth factors that are associated with cellular repair. Together, the data suggest that asymptomatic patients mount less pro-inflammatory and more protective immune responses against SARS-CoV-2 indicative of disease tolerance. Insights from this study highlight key immune pathways that could serve as therapeutic targets to prevent disease progression in COVID-19.


Assuntos
COVID-19/patologia , Portador Sadio/imunologia , Biomarcadores/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , COVID-19/imunologia , COVID-19/virologia , Portador Sadio/patologia , Portador Sadio/virologia , Citocinas/metabolismo , Humanos , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , SARS-CoV-2/isolamento & purificação , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo , Transcriptoma , Regulação para Cima , Fator D de Crescimento do Endotélio Vascular/metabolismo
10.
Nat Commun ; 12(1): 2606, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972557

RESUMO

Understanding resistance mechanisms to targeted therapies and immune checkpoint blockade in mutant KRAS lung cancers is critical to developing novel combination therapies and improving patient survival. Here, we show that MEK inhibition enhanced PD-L1 expression while PD-L1 blockade upregulated MAPK signaling in mutant KRAS lung tumors. Combined MEK inhibition with anti-PD-L1 synergistically reduced lung tumor growth and metastasis, but tumors eventually developed resistance to sustained combinatorial therapy. Multi-platform profiling revealed that resistant lung tumors have increased infiltration of Th17 cells, which secrete IL-17 and IL-22 cytokines to promote lung cancer cell invasiveness and MEK inhibitor resistance. Antibody depletion of IL-17A in combination with MEK inhibition and PD-L1 blockade markedly reduced therapy-resistance in vivo. Clinically, increased expression of Th17-associated genes in patients treated with PD-1 blockade predicted poorer overall survival and response in melanoma and predicated poorer response to anti-PD1 in NSCLC patients. Here we show a triple combinatorial therapeutic strategy to overcome resistance to combined MEK inhibitor and PD-L1 blockade.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Células Th17/metabolismo , Proteína Supressora de Tumor p53/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/imunologia , Sinergismo Farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/imunologia , Metástase Neoplásica , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Células Th17/imunologia , Proteína Supressora de Tumor p53/metabolismo
11.
Nat Immunol ; 22(6): 781-793, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34031617

RESUMO

Multimodal T cell profiling can enable more precise characterization of elusive cell states underlying disease. Here, we integrated single-cell RNA and surface protein data from 500,089 memory T cells to define 31 cell states from 259 individuals in a Peruvian tuberculosis (TB) progression cohort. At immune steady state >4 years after infection and disease resolution, we found that, after accounting for significant effects of age, sex, season and genetic ancestry on T cell composition, a polyfunctional type 17 helper T (TH17) cell-like effector state was reduced in abundance and function in individuals who previously progressed from Mycobacterium tuberculosis (M.tb) infection to active TB disease. These cells are capable of responding to M.tb peptides. Deconvoluting this state-uniquely identifiable with multimodal analysis-from public data demonstrated that its depletion may precede and persist beyond active disease. Our study demonstrates the power of integrative multimodal single-cell profiling to define cell states relevant to disease and other traits.


Assuntos
Memória Imunológica , Mycobacterium tuberculosis/imunologia , Células Th17/imunologia , Tuberculose Pulmonar/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Peru , RNA-Seq , Fatores Sexuais , Análise de Célula Única , Fatores Socioeconômicos , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/microbiologia , Adulto Jovem
12.
Front Immunol ; 12: 569287, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841390

RESUMO

Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against components of the basal membrane zone that lead to sub-epidermal loss of adhesion. Pruritus may be indicative of a pre-clinical stage of BP, since a subset of these patients shows serum IgG autoantibodies against BP230 and/or BP180 while chronic pruritus is increasingly common in the elderly population and is associated with a variety of dermatoses. Clinical and experimental evidence further suggests that pruritus of the elderly may be linked to autoimmunity with loss of self-tolerance against cutaneous autoantigens. Thus, the objective of this study was to determine autoreactive T cell responses against BP180 in elderly patients in comparison to patients with BP. A total of 22 elderly patients with pruritic disorders, 34 patients with bullous or non-bullous BP and 34 age-matched healthy controls were included in this study. The level of anti-BP180 and anti-BP230 IgG serum autoantibodies, Bullous Pemphigoid Disease Area Index (BPDAI), and pruritus severity were assessed for all patients and controls. For characterization of the autoreactive T cell response, peripheral blood mononuclear cells were stimulated ex vivo with recombinant BP180 proteins (NH2- and COOH-terminal domains) and the frequencies of BP180-specific T cells producing interferon-γ, interleukin (IL)-5 or IL-17 were subsequently determined by ELISpot assay. Patients with BP showed a mixed Th1/Th2 response against BP180 while autoreactive Th1 cells were identified in a minor subset of elderly patients with pruritic disorders. Furthermore, our T cell characterization revealed that therapeutic application of topical clobetasol propionate ointment in BP patients significantly reduced peripheral blood BP180-specific T cells, along with clinically improved symptoms, strongly suggesting a systemic immunosuppressive effect of this treatment.


Assuntos
Autoimunidade/imunologia , Penfigoide Bolhoso/imunologia , Prurido/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Clobetasol/uso terapêutico , Estudos de Coortes , Citocinas/imunologia , Citocinas/metabolismo , Distonina/imunologia , ELISPOT , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Colágenos não Fibrilares/imunologia , Pomadas , Penfigoide Bolhoso/complicações , Penfigoide Bolhoso/tratamento farmacológico , Prurido/complicações , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
13.
Front Immunol ; 12: 589200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841391

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is a classical murine model for Multiple Sclerosis (MS), a human autoimmune disease characterized by Th1 and Th17 responses. Numerous studies have reported that C-reactive protein (CRP) mitigates EAE severity, but studies on the relevant pathologic mechanisms are insufficient. Our previous study found that CRP suppresses Th1 response directly by receptor binding on naïve T cells; however, we did not observe the effect on Th17 response at that time; thus it remains unclear whether CRP could regulate Th17 response. In this study, we verified the downregulation of Th17 response by a single-dose CRP injection in MOG-immunized EAE mice in vivo while the direct and indirect effects of CRP on Th17 response were differentiated by comparing its actions on isolated CD4+ T cells and splenocytes in vitro, respectively. Moreover, the immune cell composition was examined in the blood and CNS (Central Nervous System), and a blood (monocytes) to CNS (dendritic cells) infiltration pathway is established in the course of EAE development. The infiltrated monocyte derived DCs (moDCs) were proved to be the only candidate antigen presenting cells to execute CRP's function. Conversely, the decrease of Th17 responses caused by CRP disappeared in the above in vivo and in vitro studies with FcγR2B-/- mice, indicating that FcγR2B expressed on moDCs mediates CRP function. Furthermore, peripheral blood monocytes were isolated and induced to establish moDCs, which were used to demonstrate that the antigen presenting ability of moDCs was attenuated by CRP through FcγR2B, and then NF-κB and ERK signaling pathways were manifested to be involved in this regulation. Ultimately, we perfected and enriched the mechanism studies of CRP in EAE remission, so we are more convinced that CRP plays a key role in protecting against EAE development, which may be a potential therapeutic target for the treatment of MS in human.


Assuntos
Apresentação do Antígeno/imunologia , Proteína C-Reativa/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunomodulação , Células Th17/imunologia , Células Th17/metabolismo , Animais , Antígeno B7-2/metabolismo , Biomarcadores , Diferenciação Celular/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental , Expressão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Imunofenotipagem , Ativação Linfocitária/imunologia , Camundongos , Monócitos , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Receptores de IgG/metabolismo , Transdução de Sinais , Baço/imunologia , Baço/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
14.
APMIS ; 129(5): 271-279, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33792109

RESUMO

There is very little knowledge about the immune responses, particularly cellular immunity to coronavirus disease 2019 (COVID-19). The main objective of this study was to evaluate the frequency of T helper (Th) cell subtypes, including Th1, Th17, and Treg cells, in moderate-to-severe and critical COVID-19 patients compared to healthy controls. Twenty-nine moderate-to-severe and 13 critical patients confirmed for COVID-19, and 15 healthy subjects were included in this study. Interferon-γ (IFN-γ)-producing Th1 and interleukin-17A-producing Th17 and Treg cells in peripheral blood were measured with flow cytometry. The frequency of Th1 and Th17 was significantly decreased in critical patients compared to healthy subjects (aMD: -2.76 and - 2.34) and moderate-to-severe patients (aMD: -1.89 and - 1.89), respectively (p < 0.05). Differences were not significant between moderate-to-severe patients and healthy subjects for both Th1 (p = 0.358) and Th17 (p = 0.535), respectively. In contrast, significant difference was not observed between study subjects regarding the frequency of Treg cells. Patients with critical COVID-19 had a markedly lower Th1/Treg and Th17/Treg ratios compared with the controls and moderate-to-severe cases. Our study showed a dysregulated balance of Th1 and Th17 cells and its relation to the severity of COVID-19.


Assuntos
COVID-19/imunologia , SARS-CoV-2/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Linfócito CD4 , COVID-19/patologia , Estado Terminal , Feminino , Citometria de Fluxo , Humanos , Interferon gama/biossíntese , Interleucina-17/biossíntese , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
15.
Nutrients ; 13(4)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924419

RESUMO

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventually, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed. Recent data have identified a potential role of the gut microbiota in mineral bone disorders. Thus, parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched in the Th17 cell-inducing taxa segmented filamentous bacteria. Furthermore, the microbiota was required for PTH to stimulate bone formation and increase bone mass, and this was dependent on bacterial production of the short-chain fatty acid butyrate. We review current knowledge on the relationship between phosphate, microbiota and CKD-MBD. Topics include microbial bioactive compounds of special interest in CKD, the impact of dietary phosphate and phosphate binders on the gut microbiota, the modulation of CKD-MBD by the microbiota and the potential therapeutic use of microbiota to treat CKD-MBD through the clinical translation of concepts from other fields of science such as the optimization of phosphorus utilization and the use of phosphate-accumulating organisms.


Assuntos
Distúrbio Mineral e Ósseo na Doença Renal Crônica/metabolismo , Microbioma Gastrointestinal/imunologia , Hiperfosfatemia/metabolismo , Fósforo na Dieta/metabolismo , Insuficiência Renal Crônica/complicações , Animais , Quelantes/administração & dosagem , Distúrbio Mineral e Ósseo na Doença Renal Crônica/imunologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/microbiologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/terapia , Modelos Animais de Doenças , Progressão da Doença , Saúde Holística , Humanos , Hiperfosfatemia/imunologia , Hiperfosfatemia/microbiologia , Hiperfosfatemia/terapia , Camundongos , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/metabolismo , Fósforo na Dieta/efeitos adversos , Fósforo na Dieta/antagonistas & inibidores , Fósforo na Dieta/sangue , Probióticos/uso terapêutico , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/terapia , Células Th17/imunologia
16.
J Clin Neurosci ; 87: 44-49, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33863532

RESUMO

BACKGROUND: Guillain-Barré syndrome (GBS) is an acquired immune-mediated inflammatory peripheral neuropathy. The immune regulation of ginkgolides have been revealed in recent years. We herein investigate the potential therapeutic effects of ginkgolides both on GBS and its animal model, experimental autoimmune neuritis (EAN). METHODS: EAN in C57BL/6 mice induced by subcutaneous injection with peripheral nerve myelin P0 protein peptide 180-199 (P0 peptide) were treated with ginkgolides at three different doses. GBS patients were randomly divided into two groups, the experimental group and the control group. The experimental group were treated with ginkgolides as soon as diagnosed. RESULTS: Our data indicated that ginkgolides administration daily ameliorated the score of EAN and delayed the peak of disease in EAN mice. Ginkgolides also down-regulated the proportions of T helper (Th) 17 cells in EAN spleens. Furthermore, we also found that administration of ginkgolides significantly decreased the levels of interferon (IFN)-γ and interleukin-12 (IL)-12 in GBS patients. CONCLUSIONS: Our results suggested that ginkgolides ameliorated the clinical score of EAN through down-regulating the proportions of Th 17 cells. Ginkgolides also suppressed inflammation response by decreasing pro-inflammatory cytokines IFN-γ and IL-12, suggesting ginkgolides had potential therapeutic effects on GBS patients and EAN in the future.


Assuntos
Ginkgolídeos/farmacologia , Síndrome de Guillain-Barré/tratamento farmacológico , Neurite Autoimune Experimental/tratamento farmacológico , Adulto , Idoso , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Ginkgolídeos/metabolismo , Ginkgolídeos/uso terapêutico , Síndrome de Guillain-Barré/imunologia , Síndrome de Guillain-Barré/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteína P0 da Mielina , Neurite Autoimune Experimental/imunologia , Neurite Autoimune Experimental/metabolismo , Nervos Periféricos , Células Th17/imunologia , Células Th17/metabolismo
17.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805762

RESUMO

Pertussis toxin (PTX) is a required co-adjuvant for experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin antigen. However, PTX's effects on EAE induced by the transfer of myelin-specific T helper cells is not known. Therefore, we investigated how PTX affects the Th17 transfer EAE model (Th17-EAE). We found that PTX significantly reduced Th17-EAE by inhibiting chemokine-receptor-dependent trafficking of Th17 cells. Strikingly, PTX also promoted the accumulation of B cells in the CNS, suggesting that PTX alters the disease toward a B-cell-dependent pathology. To determine the role of B cells, we compared the effects of PTX on Th17-EAE in wild-type (WT) and B-cell-deficient (µMT) mice. Without PTX treatment, disease severity was equivalent between WT and µMT mice. In contrast, with PTX treatment, the µMT mice had significantly less disease and a reduction in pathogenic Th17 cells in the CNS compared to the WT mice. In conclusion, this study shows that PTX inhibits the migration of pathogenic Th17 cells, while promoting the accumulation of pathogenic B cells in the CNS during Th17-EAE. These data provide useful methodological information for adoptive-transfer Th17-EAE and, furthermore, describe another important experimental system to study the pathogenic mechanisms of B cells in multiple sclerosis.


Assuntos
Linfócitos B/patologia , Encefalomielite Autoimune Experimental/patologia , Toxina Pertussis/administração & dosagem , Células Th17/patologia , Transferência Adotiva/métodos , Animais , Linfócitos B/imunologia , Movimento Celular/imunologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Índice de Gravidade de Doença , Células Th17/imunologia , Células Th17/transplante
18.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924467

RESUMO

Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II (CII) in DBA/1 mice as a collagen-induced arthritis (CIA) model. After the establishment of the CIA, kurarinone was given orally from day 21 to 42 (100 mg/kg/day) followed by determination of the severity based on a symptom scoring scale and with histopathology. Levels of cytokines, anti-CII antibodies, and the proliferation and lineages of T cells from the draining lymph nodes were measured using ELISA and flow cytometry, respectively. The expressional changes, including STAT1, STAT3, Nrf2, KEAP-1, and heme oxygenase-1 (HO-1) changes in the paw tissues, were evaluated by Western blot assay. Oxidative stress featured with malondiadehyde (MDA) and hydrogen peroxide (H2O2) activities in paw tissues were also evaluated. Results showed that kurarinone treatment reduced arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines, TNF-α, IL-6, IFN-γ, and IL-17A, in the serum and paw tissues. T cell proliferation was also reduced by kurarinone even under the stimulation of CII and anti-CD3 antibody. In addition, kurarinone reduced STAT1 and STAT3 phosphorylation and the proportions of Th1 and Th17 cells in lymph nodes. Moreover, kurarinone suppressed the production of MDA and H2O2. All while promoting enzymatic activities of key antioxidant enzymes, SOD and GSH-Px. In the paw tissues, upregulation of Nrf-2 and HO-1, and downregulation of KEAP-1 were observed. Overall, kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway. These beneficial effects in CIA mice contributed to the amelioration of their arthritis, indicating that kurarinone might be an adjunct treatment option for rheumatoid arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Flavonoides/uso terapêutico , Animais , Antioxidantes/metabolismo , Bovinos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas , Colágeno Tipo II , Citocinas/sangue , Citocinas/metabolismo , Feminino , Flavonoides/farmacologia , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Mediadores da Inflamação/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Malondialdeído/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Superóxido Dismutase/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
19.
Molecules ; 26(7)2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33805933

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disease mainly affecting the synovial joints. A highly potent antagonist of C-C chemokine receptor 5 (CCR5), maraviroc (MVC), plays an essential role in treating several infectious diseases but has not yet been evaluated for its potential effects on RA development. This study focused on evaluating the therapeutic potential of MVC on collagen-induced arthritis (CIA) in DBA/1J mice. Following CIA induction, animals were treated intraperitoneally with MVC (50 mg/kg) daily from day 21 until day 35 and evaluated for clinical score and histopathological changes in arthritic inflammation. We further investigated the effect of MVC on Th9 (IL-9, IRF-4, and GATA3) and Th17 (IL-21R, IL-17A, and RORγT) cells, TNF-α, and RANTES in CD8+ T cells in the spleen using flow cytometry. We also assessed the effect of MVC on mRNA and protein levels of IL-9, IL-17A, RORγT, and GATA3 in knee tissues using RT-PCR and western blot analysis. MVC treatment in CIA mice attenuated the clinical and histological severity of inflammatory arthritis, and it substantially decreased IL-9, IRF4, IL-21R, IL-17A, RORγT, TNF-α, and RANTES production but increased GATA3 production in CD8+ T cells. We further observed that MVC treatment decreased IL-9, IL-17A, and RORγt mRNA and protein levels and increased those of GATA3. This study elucidates the capacity of MVC to ameliorate the clinical and histological signs of CIA by reducing pro-inflammatory responses, suggesting that MVC may have novel therapeutic uses in the treatment of RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Maraviroc/farmacologia , Receptores CCR5/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Citocinas/imunologia , Fator de Transcrição GATA3/imunologia , Masculino , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Células Th17/imunologia , Células Th17/patologia , Receptor Toll-Like 9/imunologia
20.
Int J Mol Sci ; 22(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916809

RESUMO

Chronic graft-versus-host disease (cGVHD) is one of the most frequent complications experienced after allogeneic hematopoietic stem cell transplantation. Reportedly, dysbiosis and severe damage to the microbiome are also closely associated with GVHD. Herein, we aimed to elucidate the positive and negative effects of the administration of various antibiotics in a murine model of cGVHD. For allogeneic bone marrow transplantation (allo-BMT), bone marrow from B10.D2 mice were transplanted in BALB/c mice to induce cGVHD. The cGVHD mice were orally administered ampicillin, gentamicin (GM), fradiomycin, vancomycin, or the solvent vehicle (control group). Among the antibiotic-treated mice, the systemic cGVHD phenotypes and ocular cGVHD manifestations were suppressed significantly in GM-treated mice compared to that in control mice. Inflammatory cell infiltration and fibrosis in cGVHD-targeted organs were significantly attenuated in GM-treated mice. Although regulatory T cells were retained at greater levels in GM-treated mice, there were significantly fewer Th17 cells and interleukin (IL)-6-producing macrophages in cGVHD-targeted organs in these mice. Collectively, our results revealed that orally administered GM may exert positive effects in a cGVHD mouse model.


Assuntos
Antibacterianos/farmacologia , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/tratamento farmacológico , Administração Oral , Aloenxertos , Animais , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Interleucina-6/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/imunologia , Células Th17/patologia
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