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1.
Aging Clin Exp Res ; 32(10): 2115-2131, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32865757

RESUMO

BACKGROUND: In December 2019, a novel human-infecting coronavirus, SARS-CoV-2, had emerged. The WHO has classified the epidemic as a "public health emergency of international concern". A dramatic situation has unfolded with thousands of deaths, occurring mainly in the aged and very ill people. Epidemiological studies suggest that immune system function is impaired in elderly individuals and these subjects often present a deficiency in fat-soluble and hydrosoluble vitamins. METHODS: We searched for reviews describing the characteristics of autoimmune diseases and the available therapeutic protocols for their treatment. We set them as a paradigm with the purpose to uncover common pathogenetic mechanisms between these pathological conditions and SARS-CoV-2 infection. Furthermore, we searched for studies describing the possible efficacy of vitamins A, D, E, and C in improving the immune system function. RESULTS: SARS-CoV-2 infection induces strong immune system dysfunction characterized by the development of an intense proinflammatory response in the host, and the development of a life-threatening condition defined as cytokine release syndrome (CRS). This leads to acute respiratory syndrome (ARDS), mainly in aged people. High mortality and lethality rates have been observed in elderly subjects with CoV-2-related infection. CONCLUSIONS: Vitamins may shift the proinflammatory Th17-mediated immune response arising in autoimmune diseases towards a T-cell regulatory phenotype. This review discusses the possible activity of vitamins A, D, E, and C in restoring normal antiviral immune system function and the potential therapeutic role of these micronutrients as part of a therapeutic strategy against SARS-CoV-2 infection.


Assuntos
Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/dietoterapia , Infecções por Coronavirus/prevenção & controle , Citocinas/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/dietoterapia , Pneumonia Viral/prevenção & controle , Vitaminas/imunologia , Vitaminas/uso terapêutico , Idoso , Ácido Ascórbico/imunologia , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Vitamina A/imunologia , Vitamina A/farmacologia , Vitamina A/uso terapêutico , Vitamina D/imunologia , Vitamina D/farmacologia , Vitamina D/uso terapêutico , Vitamina E/imunologia , Vitamina E/farmacologia , Vitamina E/uso terapêutico , Vitaminas/farmacologia
2.
Front Immunol ; 11: 2056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973814

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Metformina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Metformina/efeitos adversos , Metformina/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
3.
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
4.
Mol Immunol ; 125: 162-171, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32688118

RESUMO

BACKGROUND: Baicalin has many biological properties such as anti-oxidation and anti-allergy. The current study aimed to explore the effect of Baicalin on allergic rhinitis (AR) and its potential mechanism of action. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation. Expression levels of Th17 and Treg cells-related proteins in nasal mucosa and peripheral blood cells were detected by real-time quantitative PCR, flow cytometry and Western blot. The mice were randomly divided into Control, ovalbumin (OVA), l-Baicalin, H-Baicalin, DSGC, 3-MA, and H-Baicalin + Rapa groups. Changes of allergic rhinitis conditions and eosinophil infiltration of the mice were detected and scored by Diff-Quik staining, and histological changes were observed by Hematoxylin & Eosin (H&E) staining and Periodate Schiff (PAS) staining. Serological changes, expression levels of interleukin-17A (IL-17A), interleukin-10 (IL-10), eosinophilic cationic protein (ECP) and anti-OVA-specific antibodies were detected by Enzyme-linked immunosorbent assay (ELISA). RESULTS: Clinical case analysis found that AR patients had a Th17/Treg imbalance and activated autophagy, however, Baicalin restored Th17/Treg cell balance and inhibited autophagy in vitro. in vivo experiments demonstrated that Baicalin inhibited OVA-induced allergic nasal symptoms and the activation of autophagy pathway, which was the same as the regulation of 3-MA, while Rapa could weaken the effects of H-baicalin. Moreover, Baicalin reduced the infiltration of different inflammatory cells of the nasal lavage fluid, prevented the damages to epithelial cells, and improved nasal mucosal thickness and mucus secretion. In addition, Baicalin regulated the balance of mouse anti-OVA-specific antibody levels and expressions of Th17/Treg-associated cytokines. CONCLUSION: Our study revealed that Baicalin can be used to treat AR, and the effect is realized through inhibiting autophagy to regulate Th17/Treg cell differentiation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Autofagia/efeitos dos fármacos , Flavonoides/farmacologia , Rinite Alérgica/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Autofagia/imunologia , Humanos , Camundongos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
5.
Life Sci ; 254: 117773, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32418896

RESUMO

The disturbance of the immune homeostasis caused by infection is decisive for multiple organ dysfunction caused by sepsis. Both the th17 cell and the regulatory cell(Tregs) are important components of the immune system and play a crucial role in maintaining immune homeostasis. In this study, we explored the effect of Maresin1, an emerging specific pro-inflammatory mediator, on the balance of Th17/Treg in sepsis, and investigated the underlying mechanism. We used the male C57BL/6 mice to establish the model of sepsis-induced lung injury by cecal ligation and puncture to verify the protective effect of Maresin1. Our study showed that Maresin1 could significantly inhibit the excessive inflammatory response and promote the inflammation regression in the process of sepsis-induced acute lung injury, thereby reducing lung damage and improving lung function. These effects were accompanied with the regulation of Maresin1 on the Th17/Treg balance in the early stages of sepsis. We demonstrated that Maresin1 has a certain effect on increasing the number of Treg and decreasing the number of Th17 cells in the early stages of sepsis, which is consistent with its effect on STAT3/RORγt and STAT5/Foxp3 signal pathways. Our study elucidated for the first time the relationship between Maresin1 and Th17/Treg balance in sepsis-induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Ácidos Docosa-Hexaenoicos/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Distribuição Aleatória , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT5/imunologia , Sepse/tratamento farmacológico , Sepse/imunologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
6.
Ecotoxicol Environ Saf ; 199: 110740, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32446102

RESUMO

Dibutyl phthalate (DBP) is one of the most ubiquitous phthalate esters found in everyday products, and is receiving increased attention as an immunologic adjuvant. However, information regarding DBP-aggravated allergic asthma is still limited. This study used a mouse model sensitized with ovalbumin (OVA) to determine any adverse effects of DBP on allergic asthma. Our results reveal that allergic asthmatic mice exposed to DBP for an extended period had a significant increase in inflammatory cell infiltration; a significant increase in levels of serum immunoglobulin and T helper 2 cell (Th2) and T helper 17 cell (Th17) cytokines in lung tissue; and significant changes in lung histology and AHR, all of which are typical asthmatic symptoms. The levels of oxidative stress and levels of the neuropeptide, calcitonin gene related peptide (CGRP), were also elevated after DBP exposure. Interestingly, blocking oxidative stress by administering melatonin (MT) not only reduced oxidative stress and CGRP levels, but also ameliorated the asthmatic symptoms. Collectively, these results show that DBP exacerbates asthma-like pathologies by increasing the expression of CGRP mediated by oxidative stress.


Assuntos
Asma/induzido quimicamente , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Dibutilftalato/toxicidade , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Animais , Asma/imunologia , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
7.
Cell Prolif ; 53(6): e12827, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32406154

RESUMO

OBJECTIVES: Previously, we found that by regulating T helper (Th) cell polarization, calcitriol intervention inhibited lipopolysaccharide (LPS)-induced alveolar bone loss in an animal periodontitis model, but the underlying cellular events remain unknown. MATERIALS AND METHODS: In this study, mouse Th cells were incubated in an inflammatory environment in the presence of dendritic cells (DCs) and LPS. Then, the potential of the Th cells to undergo Th2/Th17 polarization, the RANKL expression of the polarized Th cells and the subsequent influences of the polarized Th cells on RAW264.7 cell osteoclastogenesis in response to calcitriol administration were assessed. Finally, the effects of calcitriol on antigen presentation by DCs during these cellular events were evaluated. RESULTS: In response to calcitriol administration, Th cells in an inflammatory environment exhibited an enhanced potential for Th2 polarization along with a decreased potential for Th17 polarization. In addition, RANKL expression in Th17-polarized cells was largely inhibited. Furthermore, inflammation-induced osteoclastogenesis in RAW264.7 cells was suppressed following coculture with calcitriol-treated Th cells. During these cellular events, increased expression of Th2 promoters (such as OX-40L and CCL17) and decreased expression of Th17 promoters (such as IL-23 and IL-6) were found in DCs. CONCLUSIONS: Calcitriol can inhibit osteoclastogenesis in an inflammatory environment by changing the proportion and function of Th cell subsets. Our findings suggest that calcitriol may be an effective therapeutic agent for treating periodontitis.


Assuntos
Calcitriol/farmacologia , Osteoclastos/citologia , Osteogênese/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Células Cultivadas , Células Dendríticas/imunologia , Inflamação , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/metabolismo , Fenótipo , Regiões Promotoras Genéticas , Ligante RANK/metabolismo , Células RAW 264.7 , Células Th17/imunologia , Células Th2/imunologia
8.
Am J Physiol Regul Integr Comp Physiol ; 318(6): R1036-R1046, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320265

RESUMO

T-helper (TH)17s, IL-17, and cytolytic natural killer cells (cNKs) are increased in preeclampsia and contribute to the hypertension, inflammation, and fetal growth restriction that occurs in response to placental ischemia in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. As IL-17 stimulates NK cytotoxicity in vitro, we tested the hypothesis that IL-17 inhibition in RUPP rats would decrease cNK activation as a mechanism to improve maternal and fetal outcomes. On gestation day (GD) 14, rats undergoing RUPP received a miniosmotic pump infusing IL-17RC (100 pg/day), a soluble IL-17 receptor (RUPP + IL-17RC). On GD19, mean arterial pressure (MAP) was measured in normal pregnant (NP), RUPP, and RUPP + IL-17RC rats (n = 10-12/group), animals were euthanized, and blood and tissues were collected for analysis. MAP was 30% higher in RUPP compared with NP (P < 0.0001) and was 12% lower in RUPP + IL-17RC (P = 0.0007 vs. RUPP). Placental cytolytic NK cells were 132% higher in RUPP than in NP (P = 0.04 vs. NP) and were normalized in RUPP + IL-17RC (P = 0.03 vs. RUPP). Placental levels of TNF-α, a cNK-secreted cytokine, and macrophage inflammatory protein-3α (MIP-3α), a cNK chemokine, were higher in RUPP vs. NP and lower after IL-17 blockade. Placental VEGF was lower in RUPP vs. NP and was normalized in RUPP + IL-17RC. In vitro cytolytic activity of RUPP placental NKs was higher compared with NP and was blunted in RUPP + IL-17RC NKs. Finally, both fetal weight and placental weight were lower in RUPP compared with NP, and were improved in RUPP + IL-17RC. These data identify IL-17 as a mediator of cNK activation in response to placental ischemia during pregnancy.


Assuntos
Interleucina-17/metabolismo , Isquemia/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Placenta/irrigação sanguínea , Receptores de Interleucina-17/administração & dosagem , Animais , Pressão Arterial/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Isquemia/metabolismo , Placenta/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
9.
Proc Natl Acad Sci U S A ; 117(11): 6056-6066, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123118

RESUMO

T helper (Th) cells are CD4+ effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation. In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition. The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1. Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects. These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles. This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis.


Assuntos
Benzazepinas/farmacologia , Histona Desmetilases/metabolismo , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Pirimidinas/farmacologia , Células Th17/metabolismo , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Benzazepinas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Código das Histonas/efeitos dos fármacos , Histona Desmetilases/antagonistas & inibidores , Humanos , Interleucina-17/metabolismo , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Cultura Primária de Células , Pirimidinas/uso terapêutico , RNA-Seq , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Fatores de Transcrição/metabolismo
10.
J Agric Food Chem ; 68(9): 2664-2672, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033515

RESUMO

The immunomodulatory activity of a few Lactobacillus exopolysaccharides (EPS) has been reported. However, whether Lactobacillus EPS can promote the differentiation of CD4 T lymphocytes (CD4+T) cells into T-helper 17 cells (Th17 cells) in the Peyer's Patches (PPs) of mice has not been addressed. In this study, we found the molecular weight (Mw) of the purified EPS from L. casei ranged from 2.7 × 106 Da to 1.7 × 107 Da, and the average Mw was approximately 8.4 × 106 Da. In healthy BALB/c mice, EPS elevated the numbers of Th17 cells and levels of Th17-related cytokines. In vitro, EPS induced BMDCs to stimulate the differentiation of CD4+T cells of PPs into Th17 cells and the related cytokine secretions. Results suggest that L. casei EPS can effectively induce and promote the differentiation of CD4+T cells of PPs into Th17 cells in healthy mice and has the potential ability to improve intestinal mucosa immunity.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Lactobacillus casei/química , Nódulos Linfáticos Agregados/efeitos dos fármacos , Polissacarídeos Bacterianos/farmacologia , Células Th17/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Feminino , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Lactobacillus casei/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Peso Molecular , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/metabolismo , Células Th17/citologia , Células Th17/efeitos dos fármacos
11.
Transplantation ; 104(6): e151-e163, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32108749

RESUMO

BACKGROUND: Obliterative bronchiolitis (OB) remains the major complication limiting long-term survival of patients after lung transplantation. We aimed to explore the effects of the selective NACHT, LRR, and PYD domains-containing protein 3 (Nlrp3) inflammasome inhibitor MCC950 on the pathogenesis of OB. METHODS: Mouse orthotopic tracheal transplants were performed to mimic OB. MCC950 (50 mg/kg) or saline was intraperitoneally injected daily. The luminal occlusion rate and collagen deposition were evaluated by hematoxylin and eosin and Masson's trichrome staining, respectively. Infiltration of CD4+, CD8+ T cells, and neutrophils was detected with immunohistochemical staining. The frequencies of T helper 1 cell (Th1), T helper 17 cell (Th17), and regulatory T cells (Treg) were measured by flow cytometry. Cytokine levels were measured by ELISA kits. RESULTS: MCC950 treatment significantly inhibited Nlrp3 inflammasome activation after allogeneic tracheal transplant and markedly decreased the luminal occlusion rate and collagen deposition in the allograft. The numbers of infiltrating CD4+, CD8+ T cells, and neutrophils in the allograft were also significantly reduced by MCC950 treatment. MCC950 dramatically decreased the frequencies of Th1/Th17 cells and the levels of interferon gamma/interleukin (IL)-17A and increased the Treg cell frequencies and IL-10 level; however, these effects were abolished by the addition of IL-1ß and IL-18 both in vitro and in vivo. OB was also rescued by the addition of IL-1ß and/or IL-18. CONCLUSIONS: Blocking Nlrp3 inflammasome activation with MCC950 ameliorates OB lesions. The mechanistic analysis showed that MCC950 regulated the balance of Th1/Th17 and Treg cells and that this process is partially mediated by inhibition of IL-1ß and IL-18. Therefore, targeting the Nlrp3 inflammasome is a promising strategy for controlling OB after lung transplantation.


Assuntos
Bronquiolite Obliterante/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos/antagonistas & inibidores , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Sulfonas/farmacologia , Animais , Bronquiolite Obliterante/imunologia , Modelos Animais de Doenças , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Inflamassomos/imunologia , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Complicações Pós-Operatórias/imunologia , Sulfonas/uso terapêutico , 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 , Traqueia/transplante
12.
Biochem Pharmacol ; 174: 113822, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31987855

RESUMO

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease with complicated pathogenesis. IL-17-producing T helper cells (Th17) are important players in the RA process. Despite numerous researches have proven that microRNAs (miRNAs) are crucial to regulate autoimmune diseases including RA, the effect of miRNAs on Th17 cell differentiation and function in the RA progress is not clear. Here, our results showed that the expression of miRNA let-7g-5p was substantially lower in RA patients and CIA mice compared with healthy controls, accompanied by the increased Th17 cell population. Furthermore, the inhibition of let-7g-5p on Th17 cell differentiation and function were verified in vitro. Notably, the disease severity in CIA mice was significantly alleviated after the treatment of let-7g-5p mimics. In addition, let-7g-5p mimics treatment markedly down-regulated the frequency of Th17 cells in CIA mice. Taken together, our findings indicate that let-7g-5p can ameliorate CIA through blocking the differentiation of Th17 cells, which may be a novel strategy to treat autoimmune diseases such as RA.


Assuntos
Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Diferenciação Celular/fisiologia , MicroRNAs/biossíntese , Células Th17/metabolismo , Idoso , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , Pessoa de Meia-Idade , Mimetismo Molecular/efeitos dos fármacos , Mimetismo Molecular/fisiologia , Células Th17/efeitos dos fármacos , Células Th17/patologia
13.
Am J Pathol ; 190(1): 125-133, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669306

RESUMO

Neuroinflammation plays an important role in the pathogenesis of ocular surface disease, including dry eye disease (DED), but little is known about the contribution of substance P (SP) to DED. In this study, we investigated the expression of SP at the ocular surface and evaluated its effect on maturation of antigen-presenting cells (APCs), the key cell component involved in the induction of type 17 helper T-cell (Th17) response in DED. The effect of topical blockade of SP signaling was further investigated using neurokinin-1 receptor (NK1R) inhibitors on APC maturation, Th17 cell activation, and disease severity in a mouse model of DED. The results demonstrate that SP is constitutively expressed at the ocular surface, and trigeminal ganglion neurons are the major source of SP in DED. SP derived from trigeminal ganglion enhanced the expression of major histocompatibility complex class II maturation marker by bone marrow-derived dendritic cells, an effect that is abrogated by blockade of SP signaling using NK1R antagonist spantide. Finally, using a well-established murine model of DED, topical treatment of DED mice with NK1R antagonists CP-99,994 and L-733,060 suppressed APC acquisition of major histocompatibility complex class II, reduced Th17 cell activity, and ameliorated DED severity. These findings are of translational value, as they suggest that antagonizing NK1R-mediated SP signaling may be an effective strategy in suppressing Th17-mediated ocular surface disease.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Modelos Animais de Doenças , Síndromes do Olho Seco/prevenção & controle , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Receptores da Neurocinina-1/química , Células Th17/imunologia , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Córnea/efeitos dos fármacos , Córnea/imunologia , Síndromes do Olho Seco/imunologia , Síndromes do Olho Seco/metabolismo , Síndromes do Olho Seco/patologia , Feminino , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Th17/efeitos dos fármacos
14.
Chem Biol Interact ; 315: 108874, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669322

RESUMO

Allergic rhinitis (AR) is a type I hypersensitivity immune response and is a common chronic allergic respiratory disorder characterized by one or more nasal symptoms. Despite many studies on AR therapy, the drugs of treatment for AR remain limited in effect. In the present study, we aimed to elucidate the effects of saikosaponin A (SSA) on nasal inflammation, T helper (Th)2 and Th17 cytokines, retinoic acid-related orphan nuclear receptor (ROR)-γt, signal transducer and activator of transcription (STAT)3, and nuclear factor (NF)-κB signalings in ovalbumin (OVA)-induced AR mice model. OVA-induced AR mice exhibited increase in nasal symptoms, histological alteration, OVA-specific immunoglobulin (Ig)E/IgG1, ROR-γt, STAT3 and NF-κB signalings. However, the administration of SSA significantly decreased allergic symptoms including nasal rubbing and sneezing. Additionally, histological alterations such as mucosa layer thickness, goblet cell hyperplasia, eosinophils and mast cell infiltration in nasal tissues dramatically improved by treatment with SSA. Also, SSA treatment decreased the levels of OVA-specific IgE/IgG1 in serum and the levels of Th2 and Th17 cytokines such as interleukin (IL)-6 and IL-17 in nasal lavage fluid (NALF). Moreover, SSA inhibited the activation of transcription factor ROR-γt, STAT3 and phosphorylated STAT3 in both NALF and lung. Futher, SSA could also significantly inhibit the expressions of NF-κB p65 and phosphorylated NF-κB p65 in NALF and lung. These present results suggested that SSA may attenuate OVA-induced allergic rhinitis through regulating the expression of IL-6/ROR-γt/STAT3/IL-17/NF-κB signaling. The results indicate that SSA may be used as a therapeutic candidate for allergic rhinitis disease.


Assuntos
Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mucosa Nasal/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Rinite Alérgica/tratamento farmacológico , Rinite Alérgica/metabolismo , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Mucosa Nasal/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ácido Oleanólico/farmacologia , Ovalbumina/farmacologia , Rinite Alérgica/induzido quimicamente , Fator de Transcrição STAT3/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
15.
J Pharm Pharmacol ; 72(1): 92-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31724745

RESUMO

OBJECTIVES: Myricetin is a bioactive compound in many edible plants with anti-inflammatory and anticarcinogenic activity. The current study aimed to determine the protective effects and mechanism of myricetin against ulcerative colitis (UC). METHODS: Myricetin was orally administered at doses of 40 and 80 mg/kg to C57BL/6 mice with UC induced using dextran sulfate sodium. The disease-associated index and colon length were determined at the end of the experiment, the proportion of Treg, Th1 and Th17 was analysed by cytometry, and cytokines were detected using ELISA. KEY FINDINGS: Myricetin (80 mg/kg) ameliorated the severity of inflammation in acute UC and significantly improved the condition. Myricetin (80 mg/kg) elevated the levels of IL-10 and transforming growth factor ß. In addition, the proportion of regulatory T cells significantly increased in mice in the myricetin treatment group. CONCLUSIONS: Taking together, these results suggest that myricetin exhibits significant protective effects against UC and it could be used as a potential treatment for UC.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/prevenção & controle , Colo/efeitos dos fármacos , Sulfato de Dextrana , Flavonoides/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Colo/imunologia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Feminino , Interleucina-10/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/metabolismo
16.
Life Sci ; 242: 117220, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881230

RESUMO

BACKGROUND/AIMS: Previous studies have demonstrated that Galactooligosaccharides (GOS), known as "bifidus factor", has anti-inflammatory effects. Colitis, a kind of colonic inflammatory damage could be induced by different chemicals. The pathogenesis and mechanism of colitis remains unclear, and may be related to intestinal microflora, genetic susceptibility or immune factors. The aim is to explore the effects of GOS on intestinal flora and its anti-inflammatory effects in Dextran Sulfate Sodium (DSS) induced murine colitis and extrapolate the underlying mechanism. MAIN METHODS: Initially, 5% DSS was used to induced colitis by free access to drinking water for 5-7 days. Then the mice were treated with GOS 1 day after DSS treatment. Colon samples were evaluated grossly using a microscope. The percentage of Treg and Th17 cells was analyzed by flow cytometry. The levels of cytokines secretion and mRNA expression were detected by ELISA and real-time PCR. The level of protein was detected by western blot. KEY FINDINGS: GOS attenuated DSS induced body weight loss and also reduced the increase in disease index caused by DSS. GOS ameliorated DSS induced colonic histological damage. The protective effect of GOS on DSS induced colitis may be partly attributed to intestinal flora regulation and Th17/Treg imbalance. Furthermore, GOS markedly decreased cytokines (IL-6, IL-18, IL-13 and IL-33) secretion and mRNA expression in colon tissues, through inhibiting activation of NF-κB pathways. SIGNIFICANCE: GOS could prevent the DSS induced colitis through intestinal flora regulation and reduce the secretion of inflammation related cytokines relying on the NF-κB signaling pathway.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , NF-kappa B/metabolismo , Oligossacarídeos/uso terapêutico , Panteteína/análogos & derivados , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Colite/induzido quimicamente , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Microbioma Gastrointestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Panteteína/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos
17.
Food Chem Toxicol ; 137: 111091, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31883989

RESUMO

Modulation of the inflammatory response is one of the major issues of the 21st century due to its importance in the occurrence of various pathologies (cancer, autoimmune diseases, degenerative diseases) and their progression over time. Whether acute or chronic, the inflammatory response is directly related to the immune response through different subtypes of T lymphocytes. In addition, among the compounds capable of modulating the cells of the immune system, resveratrol, a polyphenol with pleiotropic biological properties, seems to be a good candidate. Indeed, resveratrol is able to alter the immune response by modulating the process of lymphocyte differentiation and subsequently diminishing the inflammatory-associated response. More specifically, thanks to its ability to act as a sirtuin-1 agonist, it can deacetylate the transcription factor STAT3 and alter nuclear factors essential to the process of lymphocyte differentiation. We present and discuss these different aspects in relation to various pathologies and how the alteration of the ratios between the different lymphocyte subtypes by resveratrol is an important element to take into account when studying its anti-inflammatory and immunomodulatory properties.


Assuntos
Resveratrol/farmacologia , Células Th17/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Citocinas/genética , Citocinas/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Células Th17/imunologia
18.
Int J Chron Obstruct Pulmon Dis ; 14: 2697-2709, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819402

RESUMO

Purpose: Elastin peptides (EP) can induce lung inflammation and emphysema. Erythromycin has been shown to decrease acute exacerbation frequency and delay lung function decline in chronic obstructive pulmonary disease patients and ameliorate emphysema in murine models; however, the mechanism remains unclear. We aimed to observe the preventive and immunomodulatory effects of erythromycin in a mouse model of EP-induced emphysema. Methods: In the in vivo study, Balb/c mice were treated with EP intranasally on day 0, and then administered erythromycin (100 mg/kg) or vehicle orally on day 1, which was continued every other day. Mice exposed to cigarette smoke were used as an emphysema positive control. The severity of emphysema and inflammation in the lungs of EP-exposed mice with or without erythromycin treatment were observed on day 40 after EP administration. In the in vitro study, naïve CD4+T cells were isolated from healthy mice spleens and stimulated by EP with or without erythromycin incubation. Flow cytometry was used to measure the proportions of Th1, Th17, and Treg cells. ELISA was used to detect cytokine levels of IFN-γ, IL-17, IL-6, and TGF-ß. Transcript levels of Ifnγ, IL17a, and Foxp3 were evaluated by qRT-PCR. Results: After exposure to EP, Th1 and Th17 cell percentages and the levels of inflammatory cytokines increased in vivo and in vitro, while Treg cells decreased in vivo. Erythromycin reduced IFN-γ, IL-17, IL-6 inflammatory cytokines, MLI, and the inflammation score in the lungs of EP-exposed mice. In vitro, erythromycin also limited Th17 and Th1 cell differentiation and downregulated transcript levels of Ifnγ and IL17a in the EP-stimulated CD4+T cells. Conclusion: The Th1 and Th17 cell responses were increased in EP-induced emphysema. Prophylactic use of erythromycin effectively ameliorated emphysema and modulated CD4+T cells responses in EP-induced lung inflammation in mice.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Citocinas/metabolismo , Elastina , Eritromicina/farmacologia , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos , Pneumonia/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/genética , Modelos Animais de Doenças , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
19.
Pak J Pharm Sci ; 32(5): 1995-2001, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31813863

RESUMO

This study was to investigate the effect of methotrexate in combination therapy by the characteristic cytokine in Th17 cells and the frequency of Tregs, which involved in the induction and pathological progress of rheumatoid arthritis (RA). The collagen-induced arthritis rats were treated with methotrexate + prednisone, methotrexate + disease-modifying rheumatic drugs (DMARDs) and methotrexate + TNFi, respectively. The following parameters were observed to evaluate three treatments: the frequency and function of Th17 cells and Tregs, the scores of X-rays, H&E staining and immunohistochemistry. For rats starting methotrexate + prednisone (low doses), the frequency and suppressive function of Th17 cells decreased while the frequency of Tregs increased, which were the same in methotrexate + TNFi. Immunohistochemical in the pathological sections of ankle joint showed the same results. The effect of methotrexate + DMARDs treatment was slightly inferior to the other combination therapies. In summary, rats treated with methotrexate + prednisone can achieve high level of Tregs and low level of Th17 cells and IL-17. Low doses of glucocorticoid suggesting a critical role in the pathogenesis of rheumatoid arthritis may have the similar effect as DMARDs.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Colágeno/farmacologia , Metotrexato/farmacologia , Animais , Artrite Reumatoide/tratamento farmacológico , Terapia Combinada/métodos , Quimioterapia Combinada/métodos , Glucocorticoides/farmacologia , Masculino , Prednisona , Ratos , Ratos Sprague-Dawley , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos
20.
Nat Commun ; 10(1): 5722, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844089

RESUMO

IL-17-producing CD8+ (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8+ T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Fumarato de Dimetilo/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Adolescente , Adulto , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Fumarato de Dimetilo/uso terapêutico , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Imunossupressores , Interleucina-17/imunologia , Interleucina-17/metabolismo , Estudos Longitudinais , Masculino , Camundongos , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Resultado do Tratamento , Adulto Jovem
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