Type 1 diabetes(T1D)is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells,which ultimately results in insulinopenia,hyperglycemia and lifelo...Type 1 diabetes(T1D)is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells,which ultimately results in insulinopenia,hyperglycemia and lifelong need for exogenous insulin therapy.In the pathophysiological landscape of T1D,T helper 17 cells(Th17 cells)and their hallmark cytokine,interleukin(IL)-17,play pivotal roles from disease onset to disease progression.In this narrative mini-review,we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D,providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction.Furthermore,we summarized the main animal and clinical studies that investigated Th17-and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.展开更多
OBJECTIVE:To explore the effect of Chang’an decoction(肠安方,CAD)of ameliorating the immune imbalances in ulcerative colitis(UC)by regulating Rab27 in the P53/high mobility group box 1 pathway.METHODS:The functions a...OBJECTIVE:To explore the effect of Chang’an decoction(肠安方,CAD)of ameliorating the immune imbalances in ulcerative colitis(UC)by regulating Rab27 in the P53/high mobility group box 1 pathway.METHODS:The functions and important signaling pathways of the Rab27-and UC-related genes were analyzed viathe use of microarray data from the gene expression omnibus database,gene ontology database,Kyoto encyclopedia of genes and genomes database and gene set enrichment analysis.Dextran sulfate sodium salt-induced colitis mouse model was used to verify the bioinformatics results.Colon length,body weight,and disease activity index were measured.Hematoxylin and eosin staining was applied to validate the histopathology.Tight junction proteins were detected by immunohistochemistry.The proportions of T helper 17 cells(Th17)and regulatory T cells(Treg)in mesenteric lymph nodes were measured viaflow cytometry.Proinflammatory cytokines like interleukin(IL)17(IL-17),IL-21 and IL-22 and anti-inflammatory cytokines like transforming growth factorβand IL-10 in the serum and colon of mice were detected by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction,respectively.The expression levels of high mobility group box 1(HMGB1),P53 and phospho-P53(P-P53)in colonic tissues were detected by immunofluorescence and Western blotting.RESULTS:Bioinformatics analysis revealed that compared with normal tissues,the expression of Rab27 was significantly increased in UC tissues.Receiver operating characteristic curve showed that Rab27 has the potential to be used as a biomarker for the diagnosis of disease activity.Enrichment analysis showed that UC and Rab27 were mainly associated with small molecule transport,nutrient metabolism,transmembrane transport and the downstream pathway of P53.According to animal experiments,the expression of Rab27 was increased in UC tissues,which aggravated the colonic pathological damage,activated the expression of HMGB1,and also leaded to the imbalance of Th17 and Treg cells.After CAD intervention,Rab27 overexpression,weight loss,colon shortening,and pathological damage were substantial reduced,the expression of tight junction proteins,zona occludens 1 and Occludin were increased.The effect of CAD at high-dose was more obvious.In addition,CAD upgraded the number of Treg cells and the production of TGF-βand IL-10,while decreasing the number of Th17 cells and the expression of inflammatory cytokines(IL-17,IL-21,and IL-22).Moreover,colon inflammation was alleviated by CAD,as indicated by the regulation of HMGB1 and P-P53 expression.CONCLUSION:The expression of Rab27,HMGB1 and P-P53 could be decreased by CAD,and the balance of Th17 and Treg cells as well as their related cytokines could be regulated by CAD.展开更多
Anthocyanin,as a typical food bioactive molecule,is capable of reversing inflammatory,oxidative and allergic condition thus contributes to intestinal health.We were wondering whether anthocyanin has influence on the i...Anthocyanin,as a typical food bioactive molecule,is capable of reversing inflammatory,oxidative and allergic condition thus contributes to intestinal health.We were wondering whether anthocyanin has influence on the infiltration of inflammatory cells into the intestinal mucosa and thus help enhancing intestinal barrier which could be damaged in some metabolic diseases.In this study,the influence of anthocyanin(administered orally)on the alterations(including structure and permeability)of the intestinal mucosa in mice in response to a high fat-high cholesterol(HFHC)diet was investigated.Primary T helper 17(Th17)cells were isolated from mouse intestine tissues to observe the modulatory role of anthocyanin through the transcription phosphorylated STAT 3(p-STAT3).The results indicated that anthocyanin significantly alleviated HFHC-induced impairment in the intestinal structures and permeability in a dose-dependent manner;moreover,anthocyanin appeared to inhibit HFHC induced the expression of p-STAT3,thereby disturbing Th17 cell differentiation.In high-fat diet(HFD,cholesterol level non-modified)-challenged mice selective p-STAT3 inhibitor significantly reversed the effects of anthocyanin,which were decreased amount of interleukin(IL)-17A(produced and released from Th17 cells)and the protected intestinal structure/function.In summary,the results of this study suggest that anthocyanin may attenuate the damage of intestinal barrier in HFHC mice through regulating intestinal STAT3-Th17-IL-17A signal transduction pathway.展开更多
BACKGROUND Post-infectious irritable bowel syndrome(PI-IBS)is generally regarded as a functional disease.Several recent studies have reported the involvement of lowgrade inflammation and immunological dysfunction in P...BACKGROUND Post-infectious irritable bowel syndrome(PI-IBS)is generally regarded as a functional disease.Several recent studies have reported the involvement of lowgrade inflammation and immunological dysfunction in PI-IBS.T helper 17(Th17)polarization occurs in IBS.Adenosine and its receptors participate in intestinal inflammation and immune regulation.AIM To investigate the role of Th17 polarization of CD4+T cells regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS A PI-IBS model was established by infecting mice with Trichinella spiralis.The intestinal A2AR and CD4+T lymphocytes were detected by immunohistochemistry,and the inflammatory cytokines were detected by enzyme-linked immunoassay.CD4+T lymphocytes present in the animal’s spleen were separated and cultured with or without A2AR agonist and antagonist.Western blotting and real-time quantitative polymerase chain reaction were performed to determine the effect of A2AR on the cells and intestinal tissue.Cytokine production was determined.The protein and mRNA levels of A2AR associated signaling pathway molecules were also evaluated.Furthermore,A2AR agonist and antagonist were injected into the mouse model and the clinical features were observed.RESULTS The PI-IBS mouse model showed increased expression of ATP and A2AR(P<0.05),and inhibition of A2AR improved the clinical features in PI-IBS,including the abdominal withdrawal reflex and colon transportation test(P<0.05).The number of intestinal CD4+T cells and interleukin-17(IL-17)protein levels increased during PI-IBS,which was reversed by administration of the A2AR antagonist(P<0.05).CD4+T cells expressed A2AR and produced IL-17 in vitro,which was regulated by the A2AR agonist and antagonist.The A2AR antagonist increased the production of IL-17 by CD4+T cells via the Janus kinase-signal transducer and activator of transcriptionreceptor-related orphan receptorγsignaling pathway.CONCLUSION The results of the present study suggested that the upregulation of A2AR increases PI-IBS by promoting the Th17 polarization of CD4+T cells.展开更多
BACKGROUND Advanced glycation end products(AGE)are a marker of various diseases including diabetes,in which they participate to vascular damages such as retinopathy,nephropathy and coronaropathy.Besides those vascular...BACKGROUND Advanced glycation end products(AGE)are a marker of various diseases including diabetes,in which they participate to vascular damages such as retinopathy,nephropathy and coronaropathy.Besides those vascular complications,AGE are involved in altered metabolism in many tissues,including adipose tissue(AT)where they contribute to reduced glucose uptake and attenuation of insulin sensitivity.AGE are known to contribute to type 1 diabetes(T1D)through promotion of interleukin(IL)-17 secreting T helper(Th17)cells.AIM To investigate whether lean adipose-derived stem cells(ASC)could be able to induce IL-17A secretion,with the help of AGE.METHODS As we have recently demonstrated that ASC are involved in Th17 cell promotion when they are harvested from obese AT,we used the same co-culture model to measure the impact of glycated human serum albumin(G-HSA)on human lean ASC interacting with blood mononuclear cells.IL-17A and pro-inflammatory cytokine secretion were measured by ELISA.Receptor of AGE(RAGE)together with intercellular adhesion molecule 1(ICAM-1),human leukocyte Antigen(HLA)-DR,cluster of differentiation(CD)41,and CD62P surface expressions were measured by cytofluorometry.Anti-RAGE specific monoclonal antibody was added to co-cultures in order to evaluate the role of RAGE in IL-17A production.RESULTS Results showed that whereas 1%G-HSA only weakly potentiated the production of IL-17A by T cells interacting with ASC harvested from obese subjects,it markedly increased IL-17A,but also interferon gamma and tumor necrosis factor alpha production in the presence of ASC harvested from lean individuals.This was associated with increased expression of RAGE and HLA-DR molecule by cocultured cells.Moreover,RAGE blockade experiments demonstrated RAGE specific involvement in lean ASC-mediated Th-17 cell activation.Finally,platelet aggregation and ICAM-1,which are known to be induced by AGE,were not involved in these processes.CONCLUSION Thus,our results demonstrated that G-HSA potentiated lean ASC-mediated IL-17A production in AT,suggesting a new mechanism by which AGE could contribute to T1D pathophysiology.展开更多
AIM： To investigate the temporal onset and dynamic interplay of CD4^＋ T helper cell subsets in experimental autoimmune encephalomyelitis （EAE）.METHODS： EAE was induced in C57BL/6 mice by im-munization with myelin...AIM： To investigate the temporal onset and dynamic interplay of CD4^＋ T helper cell subsets in experimental autoimmune encephalomyelitis （EAE）.METHODS： EAE was induced in C57BL/6 mice by im-munization with myelin oligodendrocyte glycoprotein peptide p35-55. The clinical signs were scored and the tissue samples and immune cells isolated for analysis at different phases of EAE. The expression levels of inflammatory cytokines and related transcription fac-tors were detected by quantitative reverse transcription polymerase chain reaction （PCR） and enzyme linked immunosorbant assay （ELISA）. The percentages of Th1, Th17, Th2, Treg and memory T cell subsets in EAE were analyzed by immunostaining and fow cytometry. The data were analyzed by statistical techniques.RESULTS： Quantitative real-time PCR analysis showed that EAE mice express elevated levels of Th1 [interferon gamma （ IFNγ ）, interleukin （ IL ） -12p40 ], Th17 [ IL-17 , related orphan receptor gamma （RORγ ）, IL-12p40] and Treg [ Foxp3, Epstein-Barr virus induced gene 3 （EBI3）, IL-10] genes in the central nervous system at the peak of the disease. Whereas, the expression of Th1 （ IFNγ , T-bet, IL-12p35, IL-12p40 ）, Th17 （RORγ, IL-12p40 ）, Th2 （ IL-4） and Treg （ Foxp3, EBI3） response genes was reduced in the spleen during pre-disease but gradually recovered at the later phases of EAE. ELISA and fow cytometry analyses showed an increase in Th17 re-sponse in the periphery, while Th1 response remained unchanged at the peak of disease. The mRNA levels of IFNγ, IL-17 and IL-12p40 in the brain were increased by 23 （P 〈 0.001）, 9 （P 〈 0.05） and 14 （P 〈 0.01） fold, respectively, on day 21 of EAE. Conversely, the mRNA expression of IL-10 was increased by 2 fold （P 〈 0.05） in the spleen on day 21. CD4^＋CD25^＋Foxp3＋Treg response was reduced at pre-disease but recovered to na？ve levels by disease onset. The percentage of CD25 Foxp3 regulatory T cells decreased from 7.7% in the na？ve to 3.2% （P 〈 0.05） on day 7 of EAE, which then increased to 8.4% by day 28. Moreover, the CD4＋CD127＋CD44high memory T cell response was increased during the onset and recovery phases of EAE. The memory and effector cells showed an in-verse relationship in EAE, where the memory T cells increased from 12.3% in nave to 20% by day 21, and the effector cells decreased from 32% in na？ve to 21% （P 〈 0.01） by day 21. The wild type C57BL/6 mice with EAE showed elevated levels of effector-memory T cells （TEM） with concomitant reduction in central-memory T cells （TCM）, but the EAE-resistant IL-7R defcient mice showed elevated TCM with no effect on TEM cells in EAE.CONCLUSION： Our fndings highlight the temporal on-set and dynamic interplay of effector, memory and regu-latory CD4^＋ T cell subsets and its signifcance to clinical outcome in EAE and other autoimmune diseases.展开更多
The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulate...The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.展开更多
The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the ear...The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.展开更多
To the Editor:Chronic obstructive pulmonary disease(COPD),a major global health concern,is marked by progressive airflow limitation and inflammation.While cigarette smoke(CS)is a primary cause,existing treatments rema...To the Editor:Chronic obstructive pulmonary disease(COPD),a major global health concern,is marked by progressive airflow limitation and inflammation.While cigarette smoke(CS)is a primary cause,existing treatments remain inadequate.[1]The gut-lung axis,representing a bidirectional communication pathway,emerges as a promising therapeutic target.Rhizoma Polygonati(Huang Jing),a traditional Chinese medicine,contains bioactive components including polysaccharides,known for multiple bioactivities.[2]We previously isolated a neutral polysaccharide(PSP-NP)from Polygonatum sibiricum Redoute,revealing its ability to modulate intestinal barrier function and immunity.[3]This prompts us to investigate whether PSP-NP can improve lung function via the gut-lung axis.展开更多
Background： Immune disorder is an important feature of patients with out-of-hospital cardiac arrest （OHCA） after the return of spontaneous circulation （ROSC）. We investigated the expression of circulatory T helpe...Background： Immune disorder is an important feature of patients with out-of-hospital cardiac arrest （OHCA） after the return of spontaneous circulation （ROSC）. We investigated the expression of circulatory T helper type （Th）1, Th2, and Th 17 cells to explore the early immune alteration in OHCA patients after ROSC. Methods： During July-September 2016 and March-September 2017, 65 consecutive OHCA patients with ROSC 〉 12 h and 30 healthy individuals were enrolled in this study. Clinical and 28-day survival data were collected. Peripheral blood samples were analyzed to evaluate the expression of Th1/Th2/Th 17 cells by flow cytometry from OHCA patients after ROSC on days l and 3 and from healthy individuals. Results： Compared with healthy individuals, T lymphocyte counts and Thl cell counts decreased on days 1 and 3 after ROSC （1464 [1198, 2152] vs. 779 [481, 1140] vs. 581 [324, 1118/μl,χ^2= 30.342, P 〈 0.001; 154 [90, 246] vs. 39 [19, 78] vs. 24 [12, 53]μl, χ^2 = 42.880, P〈 0.001）, and Th2 and Th17 cell counts decreased on day 3 （17.0 [10.8, 24.0] vs. 9.0 [3.0, 15.5]μl, Z= -3.228, P= 0.001; 4.7 [2.7, 9.1] vs. 2.7 [1.0, 6.5]μl, Z = -2.294, P = 0.022）. No change in CD4＋/CD3＋ lymphocyte ratio was seen on day 1 or day 3 （57.9 [49.4, 63.0] vs. 55.4 [46.5, 66.5] vs. 55.4 [50.2, 67.0]%, χ^2 = 0.171, P = 0.918）. Th1/CD4＋ lymphocyte ratio decreased on days 1 and 3 （19.0 [14.0, 24.9] vs. 9.3 [4.6, 13.9] vs. 9.5 [4.9, 13.6]%, χ^2= 25.754, P 〈 0.001）, and Th2/CD4＋ lymphocyte ratio increased on day 1 and decreased on day 3 （1.9 [1.2, 2.5] vs. 2.5 [1.6, 4.0] vs. 1.9 [1.6, 3.81%,χ^2= 6.913, P = 0.032）. Thl/Th2 cell ratio also decreased on both clays （9.4 [7.3, 13.5] vs. 3.1 [1.9, 5.6] vs. 4.2 [2.8, 5.9], χ^2 = 44.262, P 〈 0.001 ）. Despite an upward trend in the median of Th 17/CD4＋ lymphocyte ratio in OHCA patients, there was no significant difference compared with healthy individuals （0.9 [0.4, 1.2] vs. 0.7 [0.4, 1.2] vs. 0.6 [0.3, 1.01%, χ^2= 2.620, P = 0.270）. The dynamic expression of Th1/Th2/Th 17 cells on days 1 and 3 were simultaneously analyzed in 28/53 OHCA patients who survived 〉3 days; patients were divided into survivors （n = 10） and nonsurvivors （n = 18） based on 28-day survival. No significant differences in Th1/Th2/Th 17 cell counts, ratios in CD4＋ lymphocytes, and Th1/Th2 cell ratio were seen between survivors and nonsurvivors on both days （all P 〉 0.05）. There was no difference over time in both survivors and nonsurvivors （all P 〉 0.05）. Conclusion： Downregulated T lymphocyte counts, including Th1/Th2/Th17 subsets and Th1/Th2 cell ratio imbalance, occur in the early period after ROSC, that may be involved in immune dysfunction in OHCA patients.展开更多
Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4^(+)T cell subsets.Despite advancements in the management of multiple sclerosis,there is a critical need for more ...Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4^(+)T cell subsets.Despite advancements in the management of multiple sclerosis,there is a critical need for more effective and safer treatments.In the present study,we administered Lycium barbarum glycopeptide to a mouse model of experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and evaluated its effects on pathogenic CD4^(+)T cell activation both in vivo and in vitro.Lycium barbarum glycopeptide significantly mitigated the clinical severity of experimental autoimmune encephalomyelitis,as demonstrated by reduced demyelination and neuroinflammation.Moreover,Lycium barbarum glycopeptide treatment decreased the infiltration of peripheral leukocytes into the central nervous system and suppressed pro-inflammatory cytokine expression.Lycium barbarum glycopeptide also modulated pathogenic CD4^(+)T cell activation by inhibiting T helper 1/T helper 17 cell differentiation while promoting regulatory T cell expansion.Notably,no side effects were observed,suggesting the long-term safety and tolerability of Lycium barbarum glycopeptide.Furthermore,RNA sequencing data indicated that Lycium barbarum glycopeptide inhibits activator protein-1,an essential regulator of T cell activation and differentiation.This finding was supported by the reversal of T helper/T helper 17 cell response suppression upon AP-1 blockade.Collectively,these results highlight the potential of Lycium barbarum glycopeptide as an innovative therapeutic agent for CD4^(+)T cell-associated autoimmune or inflammatory diseases,such as multiple sclerosis.展开更多
Background:Integrins facilitate binding to the extracellular matrix and other cells.Their subunit β2 is exclusively expressed by leukocytes,binds to the intercellular cell adhesion molecule 1(ICAM-1),and is pivotal f...Background:Integrins facilitate binding to the extracellular matrix and other cells.Their subunit β2 is exclusively expressed by leukocytes,binds to the intercellular cell adhesion molecule 1(ICAM-1),and is pivotal for their recruitment to sites of inflammation such as the atherosclerotic plaque.Methods:To investigate β2-integrin-mediated adhesiveness,a well-established assay for human whole blood was adapted for the analysis of murine T cell subsets.Changes in avidity and affinity were assessed by incubation of murine complexes ICAM-1 in murine whole blood and consecutive stimulation with PMA and Mg^(2+)/EGTA.Underlying signaling pathways in β2-integrin-mediated adhesiveness upon chemokine stimulation with CCL-19 were identified by incubation with reducing substances,and a Ca^(2+)chelator and ROS and Ca^(2+)measurements were carried out.Results:Incubation of murine whole blood with PMA leads to 30-fold and Mg^(2+)/EGTA to 65-fold increase in β2-integrin-mediated adhesiveness of T cells.Specificity of the assay was proven by preincubation of a blocking antibody,leading to a 60%reduction in adhesion capacity.ROS species and Ca^(2+)are crucial for chemokine-mediated β2-integrin activation.In vivo relevance was proven by induction of T cell adhesiveness in whole blood of mice upon myocardial infarction.Conclusions:Our assay allows specific quantification of β2-integrin-mediated affinity and avidity of T cells in whole blood samples.In congruence to human adhesion,these mechanisms are ROS and Ca^(2+)dependent and significantly elevated after myocardial infarction.Our refined and robust assay may be of particular use in phenotyping involved mechanisms in T cell activation in atherosclerotic cardiovascular disease.展开更多
基金Supported by the European Union-NextGenerationEU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘Type 1 diabetes(T1D)is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells,which ultimately results in insulinopenia,hyperglycemia and lifelong need for exogenous insulin therapy.In the pathophysiological landscape of T1D,T helper 17 cells(Th17 cells)and their hallmark cytokine,interleukin(IL)-17,play pivotal roles from disease onset to disease progression.In this narrative mini-review,we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D,providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction.Furthermore,we summarized the main animal and clinical studies that investigated Th17-and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.
基金Supported by Lingnan Medical Research Center of Guangzhou University of Chinese MedicineNational Natural Science Foundation of China:Mechanism of Chang’an Decoction in Intestinal Mucosal Immunity of Ulcerative Colitis on Exocrine Mediated Rab27(81903963)Natural Science Foundation of Guangdong Province:the Role of the Neuropeptide Spexin-associated Gycogen Synthase Kinase-3βSignaling Pathway in Regulating the Enteric Nervous-immune Network in Ulcerative Colitis and the Intervention Mechanism of Chang’an Formula(2018A030310614)。
文摘OBJECTIVE:To explore the effect of Chang’an decoction(肠安方,CAD)of ameliorating the immune imbalances in ulcerative colitis(UC)by regulating Rab27 in the P53/high mobility group box 1 pathway.METHODS:The functions and important signaling pathways of the Rab27-and UC-related genes were analyzed viathe use of microarray data from the gene expression omnibus database,gene ontology database,Kyoto encyclopedia of genes and genomes database and gene set enrichment analysis.Dextran sulfate sodium salt-induced colitis mouse model was used to verify the bioinformatics results.Colon length,body weight,and disease activity index were measured.Hematoxylin and eosin staining was applied to validate the histopathology.Tight junction proteins were detected by immunohistochemistry.The proportions of T helper 17 cells(Th17)and regulatory T cells(Treg)in mesenteric lymph nodes were measured viaflow cytometry.Proinflammatory cytokines like interleukin(IL)17(IL-17),IL-21 and IL-22 and anti-inflammatory cytokines like transforming growth factorβand IL-10 in the serum and colon of mice were detected by enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction,respectively.The expression levels of high mobility group box 1(HMGB1),P53 and phospho-P53(P-P53)in colonic tissues were detected by immunofluorescence and Western blotting.RESULTS:Bioinformatics analysis revealed that compared with normal tissues,the expression of Rab27 was significantly increased in UC tissues.Receiver operating characteristic curve showed that Rab27 has the potential to be used as a biomarker for the diagnosis of disease activity.Enrichment analysis showed that UC and Rab27 were mainly associated with small molecule transport,nutrient metabolism,transmembrane transport and the downstream pathway of P53.According to animal experiments,the expression of Rab27 was increased in UC tissues,which aggravated the colonic pathological damage,activated the expression of HMGB1,and also leaded to the imbalance of Th17 and Treg cells.After CAD intervention,Rab27 overexpression,weight loss,colon shortening,and pathological damage were substantial reduced,the expression of tight junction proteins,zona occludens 1 and Occludin were increased.The effect of CAD at high-dose was more obvious.In addition,CAD upgraded the number of Treg cells and the production of TGF-βand IL-10,while decreasing the number of Th17 cells and the expression of inflammatory cytokines(IL-17,IL-21,and IL-22).Moreover,colon inflammation was alleviated by CAD,as indicated by the regulation of HMGB1 and P-P53 expression.CONCLUSION:The expression of Rab27,HMGB1 and P-P53 could be decreased by CAD,and the balance of Th17 and Treg cells as well as their related cytokines could be regulated by CAD.
基金supported by the National Natural Science Foundation of China(81973022 and 81730090)。
文摘Anthocyanin,as a typical food bioactive molecule,is capable of reversing inflammatory,oxidative and allergic condition thus contributes to intestinal health.We were wondering whether anthocyanin has influence on the infiltration of inflammatory cells into the intestinal mucosa and thus help enhancing intestinal barrier which could be damaged in some metabolic diseases.In this study,the influence of anthocyanin(administered orally)on the alterations(including structure and permeability)of the intestinal mucosa in mice in response to a high fat-high cholesterol(HFHC)diet was investigated.Primary T helper 17(Th17)cells were isolated from mouse intestine tissues to observe the modulatory role of anthocyanin through the transcription phosphorylated STAT 3(p-STAT3).The results indicated that anthocyanin significantly alleviated HFHC-induced impairment in the intestinal structures and permeability in a dose-dependent manner;moreover,anthocyanin appeared to inhibit HFHC induced the expression of p-STAT3,thereby disturbing Th17 cell differentiation.In high-fat diet(HFD,cholesterol level non-modified)-challenged mice selective p-STAT3 inhibitor significantly reversed the effects of anthocyanin,which were decreased amount of interleukin(IL)-17A(produced and released from Th17 cells)and the protected intestinal structure/function.In summary,the results of this study suggest that anthocyanin may attenuate the damage of intestinal barrier in HFHC mice through regulating intestinal STAT3-Th17-IL-17A signal transduction pathway.
基金Supported by National Natural Science Foundation of China,No.81160057,No.81860102,and No.82060102.
文摘BACKGROUND Post-infectious irritable bowel syndrome(PI-IBS)is generally regarded as a functional disease.Several recent studies have reported the involvement of lowgrade inflammation and immunological dysfunction in PI-IBS.T helper 17(Th17)polarization occurs in IBS.Adenosine and its receptors participate in intestinal inflammation and immune regulation.AIM To investigate the role of Th17 polarization of CD4+T cells regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS A PI-IBS model was established by infecting mice with Trichinella spiralis.The intestinal A2AR and CD4+T lymphocytes were detected by immunohistochemistry,and the inflammatory cytokines were detected by enzyme-linked immunoassay.CD4+T lymphocytes present in the animal’s spleen were separated and cultured with or without A2AR agonist and antagonist.Western blotting and real-time quantitative polymerase chain reaction were performed to determine the effect of A2AR on the cells and intestinal tissue.Cytokine production was determined.The protein and mRNA levels of A2AR associated signaling pathway molecules were also evaluated.Furthermore,A2AR agonist and antagonist were injected into the mouse model and the clinical features were observed.RESULTS The PI-IBS mouse model showed increased expression of ATP and A2AR(P<0.05),and inhibition of A2AR improved the clinical features in PI-IBS,including the abdominal withdrawal reflex and colon transportation test(P<0.05).The number of intestinal CD4+T cells and interleukin-17(IL-17)protein levels increased during PI-IBS,which was reversed by administration of the A2AR antagonist(P<0.05).CD4+T cells expressed A2AR and produced IL-17 in vitro,which was regulated by the A2AR agonist and antagonist.The A2AR antagonist increased the production of IL-17 by CD4+T cells via the Janus kinase-signal transducer and activator of transcriptionreceptor-related orphan receptorγsignaling pathway.CONCLUSION The results of the present study suggested that the upregulation of A2AR increases PI-IBS by promoting the Th17 polarization of CD4+T cells.
文摘BACKGROUND Advanced glycation end products(AGE)are a marker of various diseases including diabetes,in which they participate to vascular damages such as retinopathy,nephropathy and coronaropathy.Besides those vascular complications,AGE are involved in altered metabolism in many tissues,including adipose tissue(AT)where they contribute to reduced glucose uptake and attenuation of insulin sensitivity.AGE are known to contribute to type 1 diabetes(T1D)through promotion of interleukin(IL)-17 secreting T helper(Th17)cells.AIM To investigate whether lean adipose-derived stem cells(ASC)could be able to induce IL-17A secretion,with the help of AGE.METHODS As we have recently demonstrated that ASC are involved in Th17 cell promotion when they are harvested from obese AT,we used the same co-culture model to measure the impact of glycated human serum albumin(G-HSA)on human lean ASC interacting with blood mononuclear cells.IL-17A and pro-inflammatory cytokine secretion were measured by ELISA.Receptor of AGE(RAGE)together with intercellular adhesion molecule 1(ICAM-1),human leukocyte Antigen(HLA)-DR,cluster of differentiation(CD)41,and CD62P surface expressions were measured by cytofluorometry.Anti-RAGE specific monoclonal antibody was added to co-cultures in order to evaluate the role of RAGE in IL-17A production.RESULTS Results showed that whereas 1%G-HSA only weakly potentiated the production of IL-17A by T cells interacting with ASC harvested from obese subjects,it markedly increased IL-17A,but also interferon gamma and tumor necrosis factor alpha production in the presence of ASC harvested from lean individuals.This was associated with increased expression of RAGE and HLA-DR molecule by cocultured cells.Moreover,RAGE blockade experiments demonstrated RAGE specific involvement in lean ASC-mediated Th-17 cell activation.Finally,platelet aggregation and ICAM-1,which are known to be induced by AGE,were not involved in these processes.CONCLUSION Thus,our results demonstrated that G-HSA potentiated lean ASC-mediated IL-17A production in AT,suggesting a new mechanism by which AGE could contribute to T1D pathophysiology.
基金Supported by Methodist Research Institute,Indiana University Health
文摘AIM： To investigate the temporal onset and dynamic interplay of CD4^＋ T helper cell subsets in experimental autoimmune encephalomyelitis （EAE）.METHODS： EAE was induced in C57BL/6 mice by im-munization with myelin oligodendrocyte glycoprotein peptide p35-55. The clinical signs were scored and the tissue samples and immune cells isolated for analysis at different phases of EAE. The expression levels of inflammatory cytokines and related transcription fac-tors were detected by quantitative reverse transcription polymerase chain reaction （PCR） and enzyme linked immunosorbant assay （ELISA）. The percentages of Th1, Th17, Th2, Treg and memory T cell subsets in EAE were analyzed by immunostaining and fow cytometry. The data were analyzed by statistical techniques.RESULTS： Quantitative real-time PCR analysis showed that EAE mice express elevated levels of Th1 [interferon gamma （ IFNγ ）, interleukin （ IL ） -12p40 ], Th17 [ IL-17 , related orphan receptor gamma （RORγ ）, IL-12p40] and Treg [ Foxp3, Epstein-Barr virus induced gene 3 （EBI3）, IL-10] genes in the central nervous system at the peak of the disease. Whereas, the expression of Th1 （ IFNγ , T-bet, IL-12p35, IL-12p40 ）, Th17 （RORγ, IL-12p40 ）, Th2 （ IL-4） and Treg （ Foxp3, EBI3） response genes was reduced in the spleen during pre-disease but gradually recovered at the later phases of EAE. ELISA and fow cytometry analyses showed an increase in Th17 re-sponse in the periphery, while Th1 response remained unchanged at the peak of disease. The mRNA levels of IFNγ, IL-17 and IL-12p40 in the brain were increased by 23 （P 〈 0.001）, 9 （P 〈 0.05） and 14 （P 〈 0.01） fold, respectively, on day 21 of EAE. Conversely, the mRNA expression of IL-10 was increased by 2 fold （P 〈 0.05） in the spleen on day 21. CD4^＋CD25^＋Foxp3＋Treg response was reduced at pre-disease but recovered to na？ve levels by disease onset. The percentage of CD25 Foxp3 regulatory T cells decreased from 7.7% in the na？ve to 3.2% （P 〈 0.05） on day 7 of EAE, which then increased to 8.4% by day 28. Moreover, the CD4＋CD127＋CD44high memory T cell response was increased during the onset and recovery phases of EAE. The memory and effector cells showed an in-verse relationship in EAE, where the memory T cells increased from 12.3% in nave to 20% by day 21, and the effector cells decreased from 32% in na？ve to 21% （P 〈 0.01） by day 21. The wild type C57BL/6 mice with EAE showed elevated levels of effector-memory T cells （TEM） with concomitant reduction in central-memory T cells （TCM）, but the EAE-resistant IL-7R defcient mice showed elevated TCM with no effect on TEM cells in EAE.CONCLUSION： Our fndings highlight the temporal on-set and dynamic interplay of effector, memory and regu-latory CD4^＋ T cell subsets and its signifcance to clinical outcome in EAE and other autoimmune diseases.
文摘The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.
基金The National Natural Science Foundation of China,Nos.30871118,30971325,81270129 and 81470268(FL)grants from Department of Science and Technology of Sichuan Province,Nos.09ZQ026-020 and 2009SZ0190(FL)
文摘The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.
基金supported by grants from the National Natural Science Foundation of China(No.82004041)the Key Project of Sichuan Provincial Department of Science and Technology(No.19ZDYF0734)the Sichuan Veterinary Medicine and Drug Innovation Group of the China Agricultural Research System(No.SCCXTD-2024-18).
文摘To the Editor:Chronic obstructive pulmonary disease(COPD),a major global health concern,is marked by progressive airflow limitation and inflammation.While cigarette smoke(CS)is a primary cause,existing treatments remain inadequate.[1]The gut-lung axis,representing a bidirectional communication pathway,emerges as a promising therapeutic target.Rhizoma Polygonati(Huang Jing),a traditional Chinese medicine,contains bioactive components including polysaccharides,known for multiple bioactivities.[2]We previously isolated a neutral polysaccharide(PSP-NP)from Polygonatum sibiricum Redoute,revealing its ability to modulate intestinal barrier function and immunity.[3]This prompts us to investigate whether PSP-NP can improve lung function via the gut-lung axis.
基金This study was supported by grants from the National Natural Science Foundation of China （No. 81372025） and the 2015 Annual Special Cultivation and Development Project for the Technology Innovation Base of the Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation （No. Z151100001615056）.
文摘Background： Immune disorder is an important feature of patients with out-of-hospital cardiac arrest （OHCA） after the return of spontaneous circulation （ROSC）. We investigated the expression of circulatory T helper type （Th）1, Th2, and Th 17 cells to explore the early immune alteration in OHCA patients after ROSC. Methods： During July-September 2016 and March-September 2017, 65 consecutive OHCA patients with ROSC 〉 12 h and 30 healthy individuals were enrolled in this study. Clinical and 28-day survival data were collected. Peripheral blood samples were analyzed to evaluate the expression of Th1/Th2/Th 17 cells by flow cytometry from OHCA patients after ROSC on days l and 3 and from healthy individuals. Results： Compared with healthy individuals, T lymphocyte counts and Thl cell counts decreased on days 1 and 3 after ROSC （1464 [1198, 2152] vs. 779 [481, 1140] vs. 581 [324, 1118/μl,χ^2= 30.342, P 〈 0.001; 154 [90, 246] vs. 39 [19, 78] vs. 24 [12, 53]μl, χ^2 = 42.880, P〈 0.001）, and Th2 and Th17 cell counts decreased on day 3 （17.0 [10.8, 24.0] vs. 9.0 [3.0, 15.5]μl, Z= -3.228, P= 0.001; 4.7 [2.7, 9.1] vs. 2.7 [1.0, 6.5]μl, Z = -2.294, P = 0.022）. No change in CD4＋/CD3＋ lymphocyte ratio was seen on day 1 or day 3 （57.9 [49.4, 63.0] vs. 55.4 [46.5, 66.5] vs. 55.4 [50.2, 67.0]%, χ^2 = 0.171, P = 0.918）. Th1/CD4＋ lymphocyte ratio decreased on days 1 and 3 （19.0 [14.0, 24.9] vs. 9.3 [4.6, 13.9] vs. 9.5 [4.9, 13.6]%, χ^2= 25.754, P 〈 0.001）, and Th2/CD4＋ lymphocyte ratio increased on day 1 and decreased on day 3 （1.9 [1.2, 2.5] vs. 2.5 [1.6, 4.0] vs. 1.9 [1.6, 3.81%,χ^2= 6.913, P = 0.032）. Thl/Th2 cell ratio also decreased on both clays （9.4 [7.3, 13.5] vs. 3.1 [1.9, 5.6] vs. 4.2 [2.8, 5.9], χ^2 = 44.262, P 〈 0.001 ）. Despite an upward trend in the median of Th 17/CD4＋ lymphocyte ratio in OHCA patients, there was no significant difference compared with healthy individuals （0.9 [0.4, 1.2] vs. 0.7 [0.4, 1.2] vs. 0.6 [0.3, 1.01%, χ^2= 2.620, P = 0.270）. The dynamic expression of Th1/Th2/Th 17 cells on days 1 and 3 were simultaneously analyzed in 28/53 OHCA patients who survived 〉3 days; patients were divided into survivors （n = 10） and nonsurvivors （n = 18） based on 28-day survival. No significant differences in Th1/Th2/Th 17 cell counts, ratios in CD4＋ lymphocytes, and Th1/Th2 cell ratio were seen between survivors and nonsurvivors on both days （all P 〉 0.05）. There was no difference over time in both survivors and nonsurvivors （all P 〉 0.05）. Conclusion： Downregulated T lymphocyte counts, including Th1/Th2/Th17 subsets and Th1/Th2 cell ratio imbalance, occur in the early period after ROSC, that may be involved in immune dysfunction in OHCA patients.
基金supported by the National Natural Science Foundational of China,Nos.U24A20692(to CJZ),82371355(to CJZ),and 82101414(to MH)National NaturalScience Foundational of China for Excellent Young Scholars,No.82022019(to CJZ)+5 种基金Sichuan Special Fund for Distinguished Young Scholars,No.24NSFJQ0052(to CJZ)The Innovationand Entrepreneurial Team of Sichuan Tianfu Emei Program,No.CZ2024018(to CJZ)Funding for Distinguished Young Scholars of Sichuan Provincial People’sHospital,No.30420230005Funding for Distinguished Young Scholars of University of Electronic Science and Technology of China,No.A1098531023601381(toCJZ)Sichuan Science and Technology Support Project,No.2023YFS0212(to BH)Project of Sichuan Provincial Health Commission,No.19PJ265(to LD).
文摘Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4^(+)T cell subsets.Despite advancements in the management of multiple sclerosis,there is a critical need for more effective and safer treatments.In the present study,we administered Lycium barbarum glycopeptide to a mouse model of experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and evaluated its effects on pathogenic CD4^(+)T cell activation both in vivo and in vitro.Lycium barbarum glycopeptide significantly mitigated the clinical severity of experimental autoimmune encephalomyelitis,as demonstrated by reduced demyelination and neuroinflammation.Moreover,Lycium barbarum glycopeptide treatment decreased the infiltration of peripheral leukocytes into the central nervous system and suppressed pro-inflammatory cytokine expression.Lycium barbarum glycopeptide also modulated pathogenic CD4^(+)T cell activation by inhibiting T helper 1/T helper 17 cell differentiation while promoting regulatory T cell expansion.Notably,no side effects were observed,suggesting the long-term safety and tolerability of Lycium barbarum glycopeptide.Furthermore,RNA sequencing data indicated that Lycium barbarum glycopeptide inhibits activator protein-1,an essential regulator of T cell activation and differentiation.This finding was supported by the reversal of T helper/T helper 17 cell response suppression upon AP-1 blockade.Collectively,these results highlight the potential of Lycium barbarum glycopeptide as an innovative therapeutic agent for CD4^(+)T cell-associated autoimmune or inflammatory diseases,such as multiple sclerosis.
基金DZHK(German Centre for Cardiovascular Research)。
文摘Background:Integrins facilitate binding to the extracellular matrix and other cells.Their subunit β2 is exclusively expressed by leukocytes,binds to the intercellular cell adhesion molecule 1(ICAM-1),and is pivotal for their recruitment to sites of inflammation such as the atherosclerotic plaque.Methods:To investigate β2-integrin-mediated adhesiveness,a well-established assay for human whole blood was adapted for the analysis of murine T cell subsets.Changes in avidity and affinity were assessed by incubation of murine complexes ICAM-1 in murine whole blood and consecutive stimulation with PMA and Mg^(2+)/EGTA.Underlying signaling pathways in β2-integrin-mediated adhesiveness upon chemokine stimulation with CCL-19 were identified by incubation with reducing substances,and a Ca^(2+)chelator and ROS and Ca^(2+)measurements were carried out.Results:Incubation of murine whole blood with PMA leads to 30-fold and Mg^(2+)/EGTA to 65-fold increase in β2-integrin-mediated adhesiveness of T cells.Specificity of the assay was proven by preincubation of a blocking antibody,leading to a 60%reduction in adhesion capacity.ROS species and Ca^(2+)are crucial for chemokine-mediated β2-integrin activation.In vivo relevance was proven by induction of T cell adhesiveness in whole blood of mice upon myocardial infarction.Conclusions:Our assay allows specific quantification of β2-integrin-mediated affinity and avidity of T cells in whole blood samples.In congruence to human adhesion,these mechanisms are ROS and Ca^(2+)dependent and significantly elevated after myocardial infarction.Our refined and robust assay may be of particular use in phenotyping involved mechanisms in T cell activation in atherosclerotic cardiovascular disease.
