scholarly journals Antagonistic Peptides That Specifically Bind to the First and Second Extracellular Loops of CCR5 and Anti-IL-23p19 Antibody Reduce Airway Inflammation by Suppressing the IL-23/Th17 Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Yingli Zhang ◽  
Rongrong Liang ◽  
Aicen Xie ◽  
Wenqian Shi ◽  
Huarong Huang ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Signaling Pathway ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Inflammatory Disorder ◽  
Mrna Levels ◽  
T Helper 17 ◽  
Mucus Production ◽  
Chronic Inflammatory Disorder ◽  
Extracellular Loops

Asthma is a heterogeneous chronic inflammatory disorder of the airways with a complex etiology, which involves a variety of cells and cellular components. Therefore, the aim of the study was to investigate the effects and mechanisms of antagonistic peptides that specifically bind to the first and second extracellular loops of CCR5 (GH and HY peptides, respectively) and anti-interleukin-23 subunit p19 (anti-IL-23p19) in the airway and thereby mediate inflammation and the IL-23/T helper 17 (Th17) cell pathway in asthmatic mice. An experimental asthma model using BALB/c mice was induced by ovalbumin (OVA) and treated with peptides that are antagonistic to CCR5 or with anti-IL-23p19. The extents of the asthmatic inflammation and mucus production were assessed. In addition, bronchoalveolar lavage fluid (BALF) was collected, the cells were counted, and the IL-4 level was detected by ELISA. The IL-23/Th17 pathway-related protein and mRNA levels in the lung tissues were measured, and the positive production rates of Th17 cells in the thymus, spleen, and peripheral blood were detected. The groups treated with one of the two peptides and/or anti-IL-23p19 showed significant reductions in allergic inflammation and mucus secretion; decreased expression levels of IL-23p19, IL-23R, IL-17A and lactoferrin (LTF); and reduced proportions of Th17 cells in the thymus, spleen, and peripheral blood. Specifically, among the four treatment groups, the anti-IL-23p19 with HY peptide group exhibited the lowest positive production rate of Th17 cells. Our data also showed a significant and positive correlation between CCR5 and IL-23p19 protein expression. These findings suggest that the administration of peptides antagonistic to CCR5 and/or anti-IL-23p19 can reduce airway inflammation in asthmatic mice, most likely through inhibition of the IL-23/Th17 signaling pathway, and the HY peptide can alleviate inflammation not only through the IL-23/Th17 pathway but also through other mechanisms that result in the regulation of inflammation.

scholarly journals Stigmasterol Restores the Balance of Treg/Th17 Cells by Activating the Butyrate-PPARγ Axis in Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuting Wen ◽  
Long He ◽  
Zhuotai Zhong ◽  
Runyuan Zhao ◽  
Senhui Weng ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Th17 Cells ◽  
Experimental Colitis ◽  
Short Chain Fatty Acids ◽  
Peroxisome Proliferator ◽  
Inflammatory Disorder ◽  
T Helper 17 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chronic Inflammatory Disorder ◽  
Immune Imbalance

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with gut microbiota disequilibrium and regulatory T (Treg)/T helper 17 (Th17) immune imbalance. Stigmasterol, a plant-derived sterol, has shown anti-inflammatory effects. Our study aimed to identify the effects of stigmasterol on experimental colitis and the related mechanisms. Stigmasterol treatment restored the Treg/Th17 balance and altered the gut microbiota in a dextran sodium sulfate (DSS)-induced colitis model. Transplantation of the faecal microbiota of stigmasterol-treated mice significantly alleviated inflammation. Additionally, stigmasterol treatment enhanced the production of gut microbiota-derived short-chain fatty acids (SCFAs), particularly butyrate. Next, human naïve CD4+ T cells sorted from IBD patients were cultured under Treg- or Th17-polarizing conditions; butyrate supplementation increased the differentiation of Tregs and decreased Th17 cell differentiation. Mechanistically, butyrate activated peroxisome proliferator-activated receptor gamma (PPARγ) and reprogrammed energy metabolism, thereby promoting Treg differentiation and inhibiting Th17 differentiation. Our results demonstrate that butyrate-mediated PPARγ activation restores the balance of Treg/Th17 cells, and this may be a possible mechanism, by which stigmasterol attenuates IBD.

scholarly journals Interleukin 17 receptor E identifies heterogeneous T helper 17 cells in peritoneal fluid of severe endometriosis patients

2021 ◽  
Author(s):  
Yanping Jiang ◽  
Lu Wang ◽  
Yaqin Peng ◽  
Jian Qin ◽  
Aili Tan ◽  
...  
Keyword(s):  
Peritoneal Fluid ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Interleukin 17 ◽  
Inflammatory Disorder ◽  
T Helper ◽  
T Helper 17 ◽  
Chronic Inflammatory Disorder ◽  
Gm Csf ◽  
Metabolic Heterogeneity

Endometriosis is a chronic inflammatory disorder resulting in pelvic pain and infertility. The role of T helper 17 (Th17) cells in endometriosis remains elusive. In this study, through detecting CXCR3, CCR4, CCR10, CCR6, interleukin-17 Receptor E (IL-17RE), and CD27, live RORγt-and-IL-17A-expressing Th17 cells were distinguished and sorted from peritoneal fluid (PF) of patients with stage III and IV endometriosis. Furthermore, we found that IL-17RE and CD27 were the labels of heterogeneous PF Th17 subsets, i.e. IL-17RE-CD27- subset, IL-17RE+CD27- subset, and IL-17RE+CD27+ subset. The former two subsets expressed higher IL-17A, GM-CSF, and IL-22 and were more proliferative than the latter subset. RNA-Seq analysis on IL-17RE+ Th17 subset and IL-17RE- Th17 subset revealed up-regulation of genes involved in oxidative phosphorylation and electron transport chain in IL-17RE+ Th17 subset relative to IL-17RE- Th17 subset. Consistently, the IL-17RE+ Th17 subset produced more adenosine triphosphate (ATP) and reactive oxygen species (ROS) than IL-17RE- Th17 subset. In conclusion, this study provides a novel method to detect and isolate live PF Th17 cells from endometriosis patients and unveils the functional and metabolic heterogeneity of PF Th17 subsets. Therefore, it sheds light on the elucidation of molecular mechanisms that modulate the function of pathological Th17 cells in endometriosis.

scholarly journals Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Vuerich ◽  
Na Wang ◽  
Ahmadreza Kalbasi ◽  
Jonathon J. Graham ◽  
Maria Serena Longhi
Keyword(s):  
Autoimmune Hepatitis ◽  
Immune Regulation ◽  
Th17 Cells ◽  
Inflammatory Responses ◽  
Calcineurin Inhibitors ◽  
Inflammatory Disorder ◽  
Disease Relapse ◽  
Regulatory Cells ◽  
Chronic Inflammatory Disorder ◽  
Therapeutic Tools

Autoimmune hepatitis (AIH) is a chronic inflammatory disorder characterized by hypergammaglobulinemia, presence of serum autoantibodies and histological features of interface hepatitis. AIH therapeutic management still relies on the administration of corticosteroids, azathioprine and other immunosuppressants like calcineurin inhibitors and mycophenolate mofetil. Withdrawal of immunosuppression often results in disease relapse, and, in some cases, therapy is ineffective or associated with serious side effects. Understanding the mechanisms underlying AIH pathogenesis is therefore of paramount importance to develop more effective and well tolerated agents capable of restoring immunotolerance to liver autoantigens. Imbalance between effector and regulatory cells permits liver damage perpetuation and progression in AIH. Impaired expression and regulation of CD39, an ectoenzyme key to immunotolerance maintenance, have been reported in Tregs and effector Th17-cells derived from AIH patients. Interference with these altered immunoregulatory pathways may open new therapeutic avenues that, in addition to limiting aberrant inflammatory responses, would also reconstitute immune homeostasis. In this review, we highlight the most recent findings in AIH immunopathogenesis and discuss how these could inform and direct the development of novel therapeutic tools.

scholarly journals Oleuropein modulates over-proliferation of keratinocytes in mice with imiquimodmediated psoriasis and inhibits differentiation of TH17 cells through the JAK3/STAT3 axis

2020 ◽  
Author(s):  
Quan Shi ◽  
Qi He ◽  
Weiming Chen ◽  
Jianwen Long ◽  
Bo Zhang
Keyword(s):  
T Cells ◽  
In Silico ◽  
Th17 Cells ◽  
Skin Lesions ◽  
Docking Studies ◽  
Inflammatory Disorder ◽  
T Helper 17 ◽  
In Silico Docking

IntroductionOleuropein (OLP) is polyphenol obtained from olive oil; it is proved in Chinese traditional medicine for its use in disorders including autoimmune and inflammatory disorders. Psoriasis (PSR) is an autoimmune and inflammatory disorder triggered by T-helper-17 (Th17) cells.Material and methodsWe developed an imiquimod (IMQ)-mediated PSR model in mice to study the anti-inflammatory role of OLP in psoriasis. The mice were given 50 mg/kg and 100 mg/kg dose of OLP. Histology was done to assess the inflammation of lesions. Western blot analysis was done for JAK3/STAT3 in isolated T cells, expression of RORgt was done by RT-PCR. The In silico molecular docking studies were done for interaction of OLP with target protein STAT3 and JAK3.ResultsTreatment of OLP attenuated proliferation in IMQ-mediated keratinocytes, improved infiltration of CD3+ cells in the skin lesions and in CD4+ and CD8+ T cells and also ameliorated the levels of cytokines. In in vitro studies in isolated T cells, OLP blocked the differentiation of Th17 cells and also the levels of IL-17 and the JAK3/STAT3 pathway. The in silico docking showed that OLP had potential binding affinity with JAK3 and STAT3 which was parallel to in vivo and in vitro findings.ConclusionsOLP ameliorates psoriasis skin lesions by blocking Th17-mediated inflammation. OLP may be an interesting molecule for treating autoimmunity in psoriasis.

Soluble levels and endogenous vascular gene expression of KLOTHO are related to inflammation in human atherosclerotic disease

2017 ◽  
Vol 131 (21) ◽  
pp. 2601-2609 ◽  
Author(s):  
Ernesto Martín-Núñez ◽  
Javier Donate-Correa ◽  
Ángel López-Castillo ◽  
Alejandro Delgado-Molinos ◽  
Carla Ferri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Serum Levels ◽  
Atherosclerotic Disease ◽  
Inflammatory Disorder ◽  
Mrna Levels ◽  
Atherosclerotic Vascular Disease ◽  
Chronic Inflammatory Disorder ◽  
Control Subjects ◽  
Inflammatory Status ◽  
Tnf Α

Atherosclerosis is a chronic inflammatory disorder affecting the artery wall. Klotho, an anti-aging factor expressed in the vessel walls that participates in the maintenance of vascular homeostasis, can be down-regulated by inflammation. In this proof-of-concept work we seek to characterize the arterial KLOTHO expression in the vascular wall, as well as the serum concentration of this protein, in a group of patients with clinical atherosclerotic disease. In addition, we aim to analyze the relationship between Klotho and inflammation. Vascular samples were obtained from 27 patients with atherosclerotic disease under an elective vascular surgery procedure, and from 11 control subjects (cadaveric organ donation programme). qRT-PCR was performed to analyze the gene expression of KLOTHO, TNF-α, IL-6, and IL-10. Serum levels of soluble KLOTHO were measured by ELISA. As compared with control subjects, serum concentrations and vascular expression of Klotho were lower in patients with atherosclerotic vascular disease, whereas inflammatory status was significantly higher. There was a negative and significant correlation between inflammatory parameters and Klotho. After controlling for the effect of other variables, partial correlation showed a direct relationship between vascular KLOTHO gene expression and IL-10 mRNA levels, whereas there was a negative association with serum LDL concentrations and vascular TNF-α expression. Our study indicates an inverse interrelationship between inflammation and Klotho in atherosclerosis. Further studies are necessary to elucidate whether the inflammatory state causes Klotho deficiency or, on the contrary, reduction of Klotho could be responsible for greater inflammation, and finally, to investigate the potential clinical relevance of this association.

scholarly journals Decreased Breg/Th17 Ratio Improved the Prognosis of Patients with Ulcerative Colitis

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Xue Bing ◽  
Liang Linlang ◽  
Chen Keyan
Keyword(s):  
Ulcerative Colitis ◽  
Peripheral Blood ◽  
Theoretical Basis ◽  
Th17 Cells ◽  
Colonic Mucosa ◽  
Quantitative Polymerase Chain Reaction ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
T Helper 17 ◽  
Gene Expressions

Objective. To investigate the effects of regulatory B (Breg) cells and T helper 17 (Th17) cells on pathogenesis of ulcerative colitis, explore the clinical significance of Breg/Th17 ratio on the prognosis of ulcerative colitis, and provide the theoretical basis for the targeted therapy, diagnosis, and prognosis of the disease. Methods. Peripheral blood and colonic mucosa were collected from patients with ulcerative colitis. Hematoxylin-eosin staining was used to observe the pathological changes of colonic mucosa. Flow cytometry was utilized to analyze the percentages of Breg cells and Th17 cells. Real-time fluorescent quantitative polymerase chain reaction and immunohistochemistry were applied to determine the expression of Breg cells-related cytokines IL-10 and Th17 cell transcription factor RORγT. Enzyme-linked immunosorbent assay was employed to detect serum IL-10 and IL-17 levels. Results. The colonic mucosa of ulcerative colitis patients presented massive inflammatory cell infiltration and hemorrhagic necrosis. The number of Breg cells and Th17 cells, the gene expressions of IL-10 and RORγT, and serum levels of IL-10 and IL-17 all increased in peripheral blood. Compared with nonremission group, the remission group showed that the percentage of Breg cells reduced, the percentage of Th17 cells increased, and thus the B10/Th17 ratio was significantly decreased in peripheral blood. In addition, serum IL-10 levels diminished, IL-17 levels increased, and thus IL-10/IL-17 ratio was remarkably reduced in remission group. B10/Th17 ratio and IL-10/IL-17 ratio were positively correlated with the severity of disease. Conclusions. Breg and Th17 cells participate in the occurrence and development of ulcerative colitis. B10/Th17 ratio and IL-10/IL-17 ratio can be used as prognostic markers for ulcerative colitis. This provides a theoretical basis for design of targeted treatment and prognosis assessment of the disease.

scholarly journals Tildrakizumab in the treatment of psoriasis: latest evidence and place in therapy

2019 ◽  
Vol 10 ◽  
pp. 204062231986565 ◽  
Author(s):  
Deeti J. Pithadia ◽  
Kelly A. Reynolds ◽  
Erica B. Lee ◽  
Wilson Liao ◽  
Jashin J. Wu
Keyword(s):  
Clinical Effectiveness ◽  
The United States ◽  
Vital Role ◽  
Phase Iii ◽  
European Medicines Agency ◽  
Inflammatory Disorder ◽  
Efficacy And Safety ◽  
T Helper 17 ◽  
Duration Of Action ◽  
Chronic Inflammatory Disorder

Psoriasis is a chronic inflammatory disorder that is clinically characterized by scaly cutaneous plaques. New evidence suggests that dysregulation of interleukin (IL)-23, a key cytokine in the T-helper-17 pathway, plays a vital role in the development of psoriatic systemic inflammation. The novel biologic medication tildrakizumab is among the first drugs with specific action against IL-23 that has recently been approved by the United States Food and Drug Administration and the European Medicines Agency for moderate-to-severe psoriasis. Tildrakizumab has been shown in large randomized controlled trials to be effective in improving skin manifestations as well as enhancing quality of life outcomes in patients with psoriasis. Its simple dosing, prolonged duration of action, and mild adverse event profile make it a practical option for patients; however, only a small number of trials have investigated the clinical effectiveness of tildrakizumab, and long-term data regarding the drug’s efficacy and safety are currently limited. Hence, further research is needed to better understand the risks and benefits of tildrakizumab. This review summarizes and analyzes phase I, phase II, and phase III clinical trials that investigate the mechanism, pharmacokinetics, efficacy, and safety of tildrakizumab. It also identifies areas in which additional studies are warranted to further elucidate the advantages of tildrakizumab over other biologic therapies.

scholarly journals Effects of thermal ablation on Treg/Th17 in hepatocellular carcinoma of mice

2019 ◽  
Vol 17 ◽  
pp. 205873921983248
Author(s):  
Shengchuan Huang ◽  
Nina Qu ◽  
Yanming Men ◽  
Zhen Liu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Peripheral Blood ◽  
Thermal Ablation ◽  
Th17 Cells ◽  
Treg Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Group Model ◽  
Mrna Levels ◽  
Model Group ◽  
Tumor Tissues

The study was aimed to explore the possible function of thermal ablation treatment on T helper 17 (Th17) cells and regulatory T (Treg) cells in transplantation of hepatocellular carcinoma in mice. In total, 60 male C57BL/6 mice were divided into control group, model group, and treat group. Flow cytometry was used to detect the frequency of Th17 and Treg cells in peripheral blood. The levels of interleukin (IL)-17, IL-23, IL-10, and transforming growth factor beta (TGF-β) in serum were detected by enzyme-linked immunosorbent assay (ELISA).The levels of IL-17, RORγt, Foxp3, and TGF-β mRNA in tumor tissues were detected by real-time fluorescence quantitative PCR (qRT-PCR). Compared with the model group, tumor size was significantly decreased after thermal ablation treatment. After treatment, the frequency of Th17 cells in peripheral blood was significantly decreased, while the frequency of Treg cells was profoundly increased ( P < 0.05). The levels of IL-17 and IL-23 were significantly downregulated, while IL-10 and TGF-β levels were upregulated ( P < 0.05). IL-17 and RORγt mRNA levels in tumor tissues were significantly decreased ( P < 0.05), and Foxp3 and TGF-β mRNA levels were significantly increased ( P < 0.05). Thermal ablation treatment plays a positive role in the treatment of hepatoma in mice through affecting the imbalance of Th17/Treg cells.

Th17 cells: A prognostic marker for MS rebound after natalizumab cessation?

2016 ◽  
Vol 23 (1) ◽  
pp. 114-118 ◽  
Author(s):  
Jürgen Haas ◽  
Katharina Schneider ◽  
Alexander Schwarz ◽  
Mirjam Korporal-Kuhnke ◽  
Simon Faller ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Prognostic Marker ◽  
Peripheral Blood ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Helper ◽  
T Helper 17 ◽  
Blood Samples ◽  
Cytokine Levels

Background: Multiple sclerosis (MS) patients are at risk of renewed disease activity after discontinuing natalizumab (NAT) treatment. Objective: Assessing the implication of T helper 17 (Th17) cells in MS reactivation after NAT cessation. Methods: We monitored frequencies of Th17 cells and interleukin (IL)-17 cytokine levels in blood samples of 57 MS patients, without, during, and after NAT exposure. Results: Frequencies of both Th17 cells and, in part, also IL-17 levels, in peripheral blood increased under prolonged NAT therapy, returned to baseline after NAT withdrawal and became almost undetectable in blood samples of individuals who experienced relapses during the wash-out phase. Conclusion: Assessing the Th17-cell/IL-17 axis might help to predict rebound MS activity after NAT withdrawal.

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