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1.
JCI Insight ; 4(21)2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672934

RESUMO

Neutrophils play critical roles during the initial phase of hepatic ischemia/reperfusion injury (HIRI). However, the regulation of neutrophil activation, infiltration, and proinflammatory cytokine secretion has not been fully elucidated. In this study, we revealed that OX40 was expressed by neutrophils, its expression in neutrophils was time-dependently upregulated following HIRI, and Ox40 knockout markedly alleviated liver injury. Compared with wild-type neutrophils, the adoptive transfer of Ox40-/- neutrophils decreased HIRI in neutrophil-depleted Rag2/Il2rg-/- or Ox40-/- mice. Moreover, consistently, the in vitro experiments showed that Ox40 not only prolonged neutrophil survival but also promoted proinflammatory cytokines, ROS production, and even neutrophil chemotaxis. Further investigation demonstrated that the knockout of Ox40 in neutrophils inhibited NF-κB signaling via the TRAF1/2/4 and IKKα/IKKß/IκBα pathways. OX40L and OX86 stimulation could enhance neutrophil activation and survival in vitro and in vivo. In conclusion, our study provides a new understanding of OX40, which is expressed not only in adaptive immune cells but also in innate immune cells, i.e., neutrophils, contributing to the activation and survival of neutrophils. These findings provide a novel potential therapeutic target for the prevention of HIRI during liver transplantation or hepatic surgery.

2.
Nat Commun ; 10(1): 4246, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534137

RESUMO

Allergic asthma is an inflammatory disorder of the airway without satisfactory traditional therapies capable of controlling the underlying pathology. New approaches that can overcome the detrimental effects of immune dysregulation are thus desirable. Here we adoptively transfer ovalbumin (OVA) peptide-primed CD4-CD8- double negative T (DNT) cells intravenously into a mouse model of OVA-induced allergic asthma to find that OVA-induced airway hyperresponsiveness, lung inflammation, mucus production and OVA-specific IgG/IgE production are significantly suppressed. The immunosuppressive function of the OVA-specific DNT cells is dependent on the inhibition of CD11b+ dendritic cell function, T follicular helper cell proliferation, and IL-21 production. Mechanistically, Lag3 contributes to MHC-II antigen recognition and trogocytosis, thereby modulating the antigen-specific immune regulation by DNT cells. The effectiveness of ex vivo-generated allergen-specific DNT cells in alleviating airway inflammation thus supports the potential utilization of DNT cell-based therapy for the treatment of allergic asthma.

3.
J Gastroenterol Hepatol ; 34(10): 1676-1684, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31146297

RESUMO

BACKGROUND AND AIM: Reported incidence and prevalence rates of autoimmune hepatitis (AIH) have been sparse and heterogeneous. The aim of this meta-analysis was to estimate the worldwide incidence and prevalence rates of AIH and reveal population difference. METHODS: Published articles on the epidemiology of AIH in PubMed, Embase, and Cochrane Library were systematically searched from inception to April 28, 2019. Two investigators independently reviewed these literatures and evaluated their quality. A random-effects model was used to pool the overall incidence and prevalence rates. The impact of population difference, gender, age, study period, study quality, diagnostic criteria, and study design was further analyzed with subgroup analysis and meta-regression. RESULTS: A total of 22 studies were included in the meta-analysis. The pooled worldwide annual incidence and prevalence of AIH were 1.37 (95% confidence interval [CI]: 0.95-1.80) and 17.44 (95% CI: 12.01-22.87) per 100 000 persons, respectively. Subgroup analysis showed that the pooled annual incidence for Asian, European, and American population was 1.31 (95% CI: 0.42-2.20), 1.37 (95% CI: 1.10-1.64), and 1.00 (95% CI: 0.44-1.56) per 100 000 persons, respectively; the pooled prevalence for Asian, European, and American population was 12.99 (95% CI: 2.05-23.92), 19.44 (95% CI: 15.63-23.24), and 22.80 (95% CI: -13.48 to 59.07) per 100 000 persons, respectively. In addition, higher incidence and prevalence rates were observed in women than men, and a higher prevalence rate was observed in elderly than young people. CONCLUSIONS: Autoimmune hepatitis is a rare disease, with a similar incidence worldwide and a higher prevalence in European and American than in Asian population.

4.
FASEB J ; 33(7): 8490-8503, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30951375

RESUMO

The liver is a central immunologic organ with a high density of myeloid and lymphoid immune cells that play important roles in the development and progression of nonalcoholic steatohepatitis (NASH). However, the immune-cell-mediated regulation of NASH and its underlying mechanisms remain obscure. In this study, Prf1null mice showed significantly higher plasma alanine transaminase levels, with increased liver fat accumulation, lobular inflammation, and focal necrosis compared with wild-type (WT) mice after 4 wk of feeding on a methionine- and choline-deficient diet (MCD) or 16 wk of feeding on a high-fat diet. Perforin deficiency promoted the M1 polarization of infiltrated monocytes. Moreover, MCD-fed Prf1null mice exhibited increased accumulation, survival, activation, and proinflammatory cytokine production of CD8 T cells but not NK cells or CD4 T cells. Adoptive transfer of CD8 T cells or NK cells from WT or Prf1null mice, together with non-CD8 cells or non-NK cells from WT mice, indicated that CD8 T-cell-derived perforin participates in the mechanism regulating liver inflammation and thus plays a protective role in the development of NASH. Perforin-deficient CD8 T cells exhibited decreased cytotoxicity toward bone marrow-derived M1 monocytes and macrophages. According to the RNA sequencing data, the perforin deficiency inhibited cell apoptosis and enhanced the activation, migration, and proinflammatory cytokine production of CD8 T cells in mice with NASH. Furthermore, we found higher plasma soluble perforin levels and hepatic perforin expression in NASH patients, suggesting clinical relevance of the findings. We have elucidated an important role for the cytotoxic immune effector molecule perforin from CD8 T cells in restricting hepatic inflammation in mice with NASH and suggest that therapies designed to maximize the function of endogenous perforin in CD8 T cells might have potential benefits as NASH treatments.-Wang, T., Sun, G., Wang, Y., Li, S., Zhao, X., Zhang, C., Jin, H., Tian, D., Liu, K., Shi, W., Tian, Y., Zhang, D. The immunoregulatory effects of CD8 T-cell-derived perforin on diet-induced nonalcoholic steatohepatitis.

5.
Cell Rep ; 25(13): 3786-3799.e4, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30590049

RESUMO

Both innate and adaptive immune cells are involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), but the crosstalk between innate and adaptive immunity is largely unknown. Here we show that compared with WT mice, OX40-/- mice exhibit decreased liver fat accumulation, lobular inflammation, and focal necrosis after feeding with diets that induce NASH. Mechanistically, OX40 deficiency suppresses Th1 and Th17 differentiation, and OX40 deficiency in T cells inhibits monocyte migration, antigen presentation, and M1 polarization. Soluble OX40 stimulation alone upregulates antigen presentation, chemokine receptor expression, and proinflammatory cytokine secretion by liver monocytes. Furthermore, plasma soluble OX40 levels are positively associated with NASH in humans, suggesting clinical relevance of the findings. In conclusion, we show a mechanism for T cell regulation of innate immune cells. OX40 is a key regulator of both intrahepatic innate and adaptive immunity, generates two-way signals, and promotes both proinflammatory monocyte and macrophage and T cell function, resulting in NASH development.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores OX40/metabolismo , Animais , Apresentação do Antígeno , Diferenciação Celular , Sobrevivência Celular , Citocinas/metabolismo , Regulação para Baixo , Humanos , Mediadores da Inflamação/metabolismo , Fígado/imunologia , Fígado/patologia , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Monócitos/patologia , Hepatopatia Gordurosa não Alcoólica/sangue , Receptores OX40/sangue , Receptores OX40/deficiência , Solubilidade , Linfócitos T/imunologia
6.
Front Pharmacol ; 9: 1528, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30670973

RESUMO

Objectives: Liver macrophages agitated by Lipopolysaccharide (LPS) can enhance immuno-inflammatory responses in the liver which mediate liver injury and result in dysfunction. Midazolam has been reported to have inhibitory effects on activated immunity and escalated inflammation, however, what the effects of midazolam on the liver injury caused by excessive immuno-inflammatory response in sepsis, and what influence it will exert on inflamed liver macrophages need to be elucidated. Methods: In the present study, LPS and galactosamine-induced acute liver injury mice were used to observe the effect of midazolam in vivo. LPS-stimulated bone marrow cells were used to evaluate the influence of midazolam on monocytes in vitro. Results: Midazolam prevented liver tissue injury and decreased serum alanine transaminase (ALT) level in LPS plus galactosamine treated mice. Mechanistically, midazolam suppressed tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) produced by LPS stimulated liver macrophages in vivo and bone marrow monocytes in vitro, and reduced the expression of major histocompatibility complex class II (MHC II), cluster of differentiation 40 and 86 (CD40 and CD86) on the cell surface. These results could be reversed by PK-11195, a peripheral benzodiazepine receptor (PBR) blocker. Conclusion: Midazolam can prevent liver from LPS-induced immune mediated liver injury by inhibiting inflammation and immune activation in liver macrophages.

7.
Cell Mol Life Sci ; 74(20): 3827-3840, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28612217

RESUMO

Adaptive immunity plays a critical role in IR and T2DM development; however, the biological mechanisms linking T cell costimulation and glucose metabolism have not been fully elucidated. In this study, we demonstrated that the costimulatory molecule OX40 controls T cell activation and IR development. Inflammatory cell accumulation and enhanced proinflammatory gene expression, as well as high OX40 expression levels on CD4+ T cells, were observed in the adipose tissues of mice with diet-induced obesity. OX40-KO mice exhibited significantly less weight gain and lower fasting glucose levels than those of WT mice, without obvious adipose tissue inflammation. The effects of OX40 on IR are mechanistically linked to the promotion of T cell activation, Th1 cell differentiation and proliferation-as well as the attenuation of Treg suppressive activity and the enhancement of proinflammatory cytokine production-in adipose tissues. Furthermore, OX40 expression on T cells was positively associated with obesity in humans, suggesting that our findings are clinically relevant. In summary, our study revealed that OX40 in CD4+ T cells is crucial for adipose tissue inflammation and IR development. Therefore, the OX40 signaling pathway may be a new target for preventing or treating obesity-related IR and T2DM.


Assuntos
Tecido Adiposo/imunologia , Inflamação/imunologia , Resistência à Insulina , Obesidade/imunologia , Receptores OX40/imunologia , Tecido Adiposo/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Humanos , Inflamação/etiologia , Inflamação/genética , Ativação Linfocitária , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/complicações , Obesidade/genética , Receptores OX40/genética , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Regulação para Cima
8.
Int Immunopharmacol ; 41: 56-65, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27816727

RESUMO

Monitoring T lymphocyte proliferation, especially in vivo, is essential for the evaluation of adaptive immune reactions. Flow cytometry-based proliferation assays have advantages in measuring cell division of different T lymphocyte subsets at the same time by multicolor labelling. In this study, we aimed to establish the use of 5-Ethynyl-2'-deoxyuridine (EdU) incorporation in vivo to monitor T lymphocyte proliferation by flow cytometry with an adoptive transfer model. We found that fixation followed by permeabilization preserved T cell surface antigens and had no obvious effects on the fluorescence intensity of APC, PE, PE-Cy7, FITC and PerCP-Cy5.5 when the concentration of the permeabilization reagents was optimized. However, the click reaction resulted in a significant decrease in the fluorescence intensity of PE and PE-Cy7, and surface staining after the click reaction improved the fluorescence intensity. Thus, an extra step of blocking with PBS with 3% FBS between the click reaction and cell surface staining is needed. Furthermore, the percentage of EdU-positive cells increased in a dose-dependent manner, and the saturated dose of EdU was 20mg/kg. Intraperitoneal and intravenous injection had no differences in lymphocyte proliferation detection with EdU in vivo. In addition, T cell proliferation measured by EdU incorporation was comparable to BrdU but was lower than CFSE labelling. In conclusion, we optimized the protocols for EdU administration in vivo and staining in vitro, providing a feasible method for the measurement of T lymphocyte proliferation with EdU incorporation by flow cytometry in vivo.


Assuntos
Desoxiuridina/análogos & derivados , Citometria de Fluxo/métodos , Coloração e Rotulagem/métodos , Linfócitos T/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Química Click , Desoxiuridina/farmacologia , Corantes Fluorescentes/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Octoxinol/farmacologia , Saponinas/farmacologia , Linfócitos T/citologia , Linfócitos T/metabolismo
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