scholarly journals The YAP/HIF-1α/miR-182/EGR2 axis is implicated in asthma severity through the control of Th17 cell differentiation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jing Zhou ◽  
Ning Zhang ◽  
Wei Zhang ◽  
Caiju Lu ◽  
Fei Xu
Keyword(s):  
Lipid Metabolism ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Airway Remodeling ◽  
Quantitative Polymerase Chain Reaction ◽  
Airflow Limitation ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Th17 Cell Differentiation

Abstract Background Asthma is a heterogeneous chronic inflammatory disease of the airway, involving reversible airflow limitation and airway remodeling. T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. However, there is limited understanding of the signaling pathways controlling Th17 cell differentiation in asthma. The aim of this study was to investigate if the Yes-associated protein (YAP)/hypoxia inducible factor-1α (HIF-1α)/microRNA-182 (miR-182)/early growth response 2 (EGR2) axis is involved in mediating Th17 cell differentiation and disease severity in asthma. Methods The study included 29 pediatric patients with asthma, 22 healthy volunteers, ovalbumin-induced murine asthma models, and mouse naive CD4+ T cells. The subpopulation of Th17 cells was examined by flow cytometry. The levels of interleukin-17A were determined by enzyme linked immunosorbent assay. Chromatin immunoprecipitation-quantitative polymerase chain reaction assays and dual-luciferase reporter gene assays were performed to examine interactions between HIF-1α and miR-182, and between miR-182 and EGR2. Results YAP, HIF-1α, and miR-182 were upregulated but EGR2 was downregulated in human and mouse peripheral blood mononuclear cells from the asthma group. Abundant expression of YAP and HIF-1α promoted miR-182 expression and then inhibited EGR2, a target of miR-182, thus enhancing Th17 differentiation and deteriorating asthma and lipid metabolism dysfunction. In addition, in vivo overexpression of EGR2 countered the promoting effect of the YAP/HIF-1α/miR-182 axis on asthma and lipid metabolism dysfunction. Conclusion These results indicate that activation of the YAP/HIF-1α/miR-182/EGR2 axis may promote Th17 cell differentiation, exacerbate asthma development, and aggravate lipid metabolism dysfunction, thus suggesting a potential therapeutic target for asthma.

scholarly journals The YAP/HIF-1α/miR-182/EGR2 Axis is Implicated in Asthma Severity by Control of Th17 Cell Differentiation

2020 ◽  
Author(s):  
Jing Zhou ◽  
Ning Zhang ◽  
Wei Zhang ◽  
Caiju Lu ◽  
Fei Xu
Keyword(s):  
Lipid Metabolism ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
Airway Remodeling ◽  
Asthma Severity ◽  
Luciferase Reporter ◽  
Th17 Cell Differentiation ◽  
Gene Assay

Abstract Background: Asthma is a heterogeneous chronic inflammatory disease of the airways, with reversible airflow limitations and airway remodeling. T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. However, there is hitherto little data about signaling pathways controlling Th17 cell differentiation in asthma. The aim of this study was to ascertain whether the YAP/HIF-1α/miR-182/EGR2 axis underpins Th17 cell differentiation and asthma severity.Methods: The study included 29 pediatric patients with asthma, 22 healthy volunteers, ovalbumin (OVA)-induced murine asthma models, and mouse naive CD4+ T. The subpopulation of Th17 cells was examined by flow cytometry. The level of IL-17A was determined by ELISA method. ChIP-qPCR assay and dual-luciferase reporter gene assay were performed to examine interaction between HIF-1α and miR-182, miR-182 and EGR2.Results: YAP, HIF-1α, and miR-182 were found to be up-regulated but EGR2 was down-regulated in human and mouse peripheral blood mononuclear cells (PBMCs) in the context of asthma. Abundant expression of YAP and HIF-1α promoted miR-182 expression and then inhibited EGR2, a target of miR-182, thus enhancing Th17 differentiation and deteriorating asthma and lipid metabolism dysfunction. In addition, in vivo findings revealed that over-expression of EGR2 undermined the promoting effect of the YAP/HIF-1α/miR-182 axis on asthma and lipid metabolism dysfunction.Conclusion: These results shed light on that the activation of the YAP/HIF-1α/miR-182/EGR2 axis may promote Th17 cell differentiation, exacerbate asthma development, and aggravate lipid metabolism dysfunction, providing a potential therapeutic target in asthma.

scholarly journals LncRNA H19 over-expression inhibited Th17 cell differentiation to relieve endometriosis through miR-342-3p/IER3 pathway

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zheying Liu ◽  
Liya Liu ◽  
Yun Zhong ◽  
Mingbo Cai ◽  
Junbi Gao ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
Luciferase Reporter ◽  
Over Expression ◽  
Th17 Cell Differentiation ◽  
Th17 Differentiation

Abstract Objective To investigate the mechanism of LncRNA H19 in Th17 cell differentiation and endometrial stromal cells (ESCs) proliferation in endometriosis (EMS). Methods LncRNA H19, miR-342-3p and IER3 expressions were detected by qRT-PCR and western blot. The percentage of Th17 cells/CD4+ T cells was detected by flow cytometry. IL-17 level was measured by ELISA. The interaction of miR-342-3p and IER3 was confirmed by Luciferase reporter assay. Results LncRNA H19 and IER3 expressions were down-regulated in mononuclear cells from peritoneal fluid (PFMCs) of patients with EMS or under Th17 differentiation conditions, whereas miR-342-3p expression was up-regulated and the percentage of Th17 cells was increased in PFMCs of patients with EMS or under Th17 differentiation conditions. Over-expression of LncRNA H19 decreased IL-17 level and the percentage of Th17 cells/CD4+ T cells. Besides, we confirmed that miR-342-3p could target to IER3 and negatively regulate IER3 expression. LncRNA H19 over-expression suppressed Th17 differentiation and ESC proliferation through regulating miR-342-3p/IER3. In vivo experiments showed LncRNA H19 over-expression suppressed the growth of Th17 cell differentiation-induced endometriosis-like lesions. Conclusion LncRNA H19 was down-regulated in PFMC of patients with EMS or under Th17 polarizing conditions, and LncRNA H19 over-expression suppressed Th17 cell differentiation and ESCs proliferation through miR-342-3p/IER3 pathway.

scholarly journals LncRNA-BG Inhibited Th17 Cells Differentiation By Targeting RORγt Protein.

2021 ◽  
Author(s):  
hanlin he ◽  
xiangjie qiu ◽  
mingming qi ◽  
Ousman Bajinka ◽  
ling qin ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
High Throughput Screening ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Gene Promoter ◽  
Luciferase Reporter ◽  
Th17 Cell Differentiation ◽  
Th17 Differentiation ◽  
Treatment And Diagnosis

Abstract Background: In our previous study, we obtained lncRNA-BG related to COPD through high-throughput screening, but we could not determine the specific mechanism involved. To this responds, here, we designed this study to verify whether lncRNA-BG could regulate the differentiation of Th17 cells and its mechanism. Methods: The interaction between lncRNA-BG and RORγt protein was predicted using bioinformatics approaches. This was then confirmed by RNA pull down and dual luciferase reporter assay. The correlation between lncRNA-BG and Th17 cell differentiation was verified among patients with COPD and in vitro culture experiment. Meanwhile, the regulatory effect of lncRNA-BG on Th17 cell differentiation was determined by regulation the expression level of lncRNA-BG. Results: LncRNA-BG could bind with RORγt protein and inhibit the differentiation of Th17 cells. LncRNA-BG was significantly negatively correlated with Th17 differentiation in patients with COPD and in vitro experiment. The decrease level of LncRNA-BG could promote Th17 differentiation, while the increase level of LncRNA-BG could inhibit Th17 differentiation. Conclusion: LncRNA-BG directly targets RORγt protein, inhibits the mutual binding of RORγt and IL-17 gene promoter, and eventually inhibits Th17 differentiation. LncRNA-BG as a potential target may confer applications in the clinical treatment and diagnosis of Th17-related diseases.

scholarly journals Mapping Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells

2021 ◽  
Author(s):  
Ankitha Shetty ◽  
Santosh D. Bhosale ◽  
Subhash Kumar Tripathi ◽  
Tanja Buchacher ◽  
Rahul Biradar ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Affinity Purification ◽  
Mass Spectrometry Analysis ◽  
Binding Partners ◽  
Th17 Cell Differentiation

Dysregulated function of Th17 cells has implications in immunodeficiencies and autoimmune disorders. Th17 cell-differentiation is orchestrated by a complex network of transcription factors, including several members of the activator protein (AP-1) family. Among these, FOSL1 and FOSL2 influence the effector responses of Th17 cells. However, the molecular mechanisms underlying their functions are unclear, owing to the poorly characterized protein interaction networks of these factors. Here, we establish the first interactomes of FOSL1 and FOSL2 in human Th17 cells, using affinity purification–mass spectrometry analysis. In addition to the known JUN proteins, we identified several novel binding partners of FOSL1 and FOSL2. Gene ontology analysis found a major fraction of these interactors to be associated with RNA binding activity, which suggests new mechanistic links. Intriguingly, 29 proteins were found to share interactions with FOSL1 and FOSL2, and these included key regulators of Th17-fate. We further validated the binding partners identified in this study by using parallel reaction monitoring targeted mass spectrometry and other methods. Our study provides key insights into the interaction-based signaling mechanisms of FOSL1 and FOSL2 that potentially govern Th17 cell-differentiation and associated pathologies.

Malignant B Cells Skew the Balance between Treg Cell and TH17 Cell Differentiation in B-Cell Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1347-1347
Author(s):  
Zhi-Zhang Yang ◽  
Anne J. Novak ◽  
Thomas E. Witzig ◽  
Stephen M. Ansell
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Th17 Cell Differentiation

Abstract Numerous clinical therapies have attempted to modulate tumor cell immunity, but for the most part, have proven unsuccessful. The inability to produce or augment an effective immune response is due in part to regulatory T (Treg) cells, which inhibit CD4 and CD8 T cell function. Our group has recently shown that Treg cell numbers are elevated in NHL tumors and that NHL B cells induce the development of Treg cells thereby inhibiting anti-tumor responses. The ability of NHL B cells to direct the cellular composition of their microenvironment is critical to our understanding of tumor immunity and we therefore wanted to determine if NHL B cells also directed the expansion or reduction of other T cell populations. IL-17-secreting CD4+ T cells (TH17), a newly characterized CD4+ T helper cell lineage, promote inflammation and play an important role in autoimmune disease. IL-17 has been shown to inhibit tumor cell growth suggesting a potential role for TH17 cells in anti-tumor immunity. We therefore set out to determine if TH17 cells were present in NHL tumors and whether or not their numbers were regulated by NHL B cells. Using unsorted mononuclear cells from malignant lymph nodes, we were unable to detect IL-17 expression in resting CD4+ T cells or CD4+ T cells activated with PMA/Ionomycin stimulation (less than 1%). However, IL-17-secreting CD4+ T cells could be detected in significant numbers in inflammatory tonsil and normal PBMCs. Interestingly, depletion of CD19+ NHL B cells from mononuclear cells obtained from patient biopsies resulted in detection of a clear population of IL-17-secreting CD4+ T cells (5%). These results suggest that NHL B cells suppress TH17 cell differentiation. The frequency of IL-17-secreting CD4+ T cells could not be further enhanced by the addition of exogenous TGF-b and IL-6, a cytokine combination favoring for TH17 differentiation, suggesting a further impairment of TH17 cell differentiation in the tumor microenvironment. In contrast, Foxp3 expression could be detected in resting CD4+ T cells (30%) and could be induced in CD4+CD25−Foxp3− T cells activated with TCR stimulation (28%). Contrary to the inhibition of TGF-b-mediated TH17 differentiation, Foxp3 expression could be dramatically upregulated by TGF-b in intratumoral CD4+ T cells (35%). In addition, lymphoma B cells strongly enhanced Foxp3 expression in intratumoral CD4+CD25−Foxp3−. Furthermore, when added together, the frequency of Foxp3+ T cells and Foxp3-inducible cells reached up to 60% of CD4+ T cells in tumor microenvironment of B-cell NHL. These findings suggest that the balance of effector TH17 cells and inhibitory Treg cells is disrupted in B-cell NHL and significantly favors the development of inhibitory Treg cells. Our data indicate that lymphoma B cells are key factor in regulating differentiation of intratumoral CD4+ T cells toward inhibitory CD4+ T cells.

scholarly journals Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation

2009 ◽  
Vol 206 (11) ◽  
pp. 2407-2416 ◽  
Author(s):  
Jyoti Das ◽  
Guangwen Ren ◽  
Liying Zhang ◽  
Arthur I. Roberts ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Th2 Cells ◽  
Th17 Cell Differentiation ◽  
Th1 And Th2

Interleukin (IL)-17–producing T helper (Th17) cells play a critical role in the pathophysiology of several autoimmune disorders. The differentiation of Th17 cells requires the simultaneous presence of an unusual combination of cytokines: IL-6, a proinflammatory cytokine, and transforming growth factor (TGF) β, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-β exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor γt, a Th17-specific transcription factor. Interestingly, in Stat-6−/−T-bet−/− mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whereas TGF-β had no effect, suggesting that TGF-β is dispensable for Th17 cell development. Consequently, BALB/c Stat-6−/−T-bet−/− mice, but not wild-type BALB/c mice, were highly susceptible to the development of experimental autoimmune encephalomyelitis, which could be blocked by anti–IL-17 antibodies but not by anti–TGF-β antibodies. Collectively, these data provide evidence that TGF-β is not directly required for the molecular orchestration of Th17 cell differentiation.

scholarly journals SKI Expression Suppresses Pathogenic Th17 Cell Response and Mitigates Experimental Autoimmune Encephalomyelitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Ping Li ◽  
Zengli Guo ◽  
Yisong Y. Wan
Keyword(s):  
Cell Differentiation ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Ectopic Expression ◽  
Transfer Model ◽  
Autoimmune Encephalomyelitis ◽  
Th17 Cell Differentiation ◽  
Experimental Autoimmune

Pathogenic Th17 cells are critically involved in many autoimmune diseases, while non-pathogenic Th17 cells are more immune regulatory. Understanding the mechanisms of the induction and maintenance of pathogenic Th17 cells will benefit the development of therapeutic treatments of related diseases. We have shown that the transforming growth factor-β (TGFβ) induced SKI degradation and dissociation from Smad4 complex is a prerequisite for TGFβ-induced Th17 cell differentiation. However, it is unclear whether and how SKI regulates pathogenic Th17 differentiation, which does not require TGFβ cytokine. Here we showed that SKI expression was downregulated during pathogenic Th17 cell differentiation and the ectopic expression of SKI abrogated the differentiation of pathogenic Th17 cells. Functionally, using a knock-in mouse model, we found ectopic SKI expression specifically in T cells prevented myelin oligodendrocyte glycoprotein peptide (MOG33–55) induced experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis. We further revealed that induced SKI expression in already differentiated pathogenic Th17 cells reduced the maintenance of Th17 program and ameliorated EAE in an adoptive T cell transfer model. Therefore, our study provides valuable insights of targeting SKI to modulate pathogenic Th17 cell function and treat Th17-related diseases.

scholarly journals Engineered Th17 cell differentiation using a photo-activatable immune modulator

2019 ◽  
Author(s):  
Bibudha Parasar ◽  
Pamela V. Chang
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Uv Light ◽  
T Cell Subsets ◽  
Light Illumination ◽  
Immune Modulator ◽  
On Demand ◽  
Th17 Cell Differentiation

AbstractT helper 17 (Th17) cells, an important subset of CD4+ T cells, help to eliminate extracellular infectious pathogens that have invaded our tissues. Despite the critical roles of Th17 cells in immunity, how the immune system regulates the production and maintenance of this cell type remains poorly understood. In particular, the plasticity of these cells, or their dynamic ability to trans-differentiate into other CD4+ T cell subsets, remains mostly uncharacterized. Here, we report a synthetic immunology approach using a photo-activatable immune modulator (PIM) to increase Th17 cell differentiation on demand with spatial and temporal precision to help elucidate this important and dynamic process. In this chemical strategy, we developed a latent agonist that, upon photochemical activation, releases a small-molecule ligand that targets the aryl hydrocarbon receptor (AhR) and ultimately induces Th17 cell differentiation. We used this chemical tool to control AhR activation with spatiotemporal precision within cells and to modulate Th17 cell differentiation on demand by using UV light illumination. We envision that this approach will enable an understanding of the dynamic functions and behaviors of Th17 cells in vivo during immune responses and in mouse models of inflammatory disease.

scholarly journals PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation

2020 ◽  
Vol 217 (10) ◽  
Author(s):  
Luis Eduardo Alves Damasceno ◽  
Douglas Silva Prado ◽  
Flavio Protasio Veras ◽  
Miriam M. Fonseca ◽  
Juliana E. Toller-Kawahisa ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Glycolytic Enzyme ◽  
Metabolic Reprogramming ◽  
Fine Tuning ◽  
Autoimmune Inflammation ◽  
Th17 Cell Differentiation ◽  
Key Factor

Th17 cell differentiation and pathogenicity depend on metabolic reprogramming inducing shifts toward glycolysis. Here, we show that the pyruvate kinase M2 (PKM2), a glycolytic enzyme required for cancer cell proliferation and tumor progression, is a key factor mediating Th17 cell differentiation and autoimmune inflammation. We found that PKM2 is highly expressed throughout the differentiation of Th17 cells in vitro and during experimental autoimmune encephalomyelitis (EAE) development. Strikingly, PKM2 is not required for the metabolic reprogramming and proliferative capacity of Th17 cells. However, T cell–specific PKM2 deletion impairs Th17 cell differentiation and ameliorates symptoms of EAE by decreasing Th17 cell–mediated inflammation and demyelination. Mechanistically, PKM2 translocates into the nucleus and interacts with STAT3, enhancing its activation and thereby increasing Th17 cell differentiation. Thus, PKM2 acts as a critical nonmetabolic regulator that fine-tunes Th17 cell differentiation and function in autoimmune-mediated inflammation.

scholarly journals Mycobacterium tuberculosis RpfE-Induced Prostaglandin E2 in Dendritic Cells Induces Th1/Th17 Cell Differentiation

2021 ◽  
Vol 22 (14) ◽  
pp. 7535
Author(s):  
Hye-Soo Park ◽  
Seunga Choi ◽  
Yong-Woo Back ◽  
Kang-In Lee ◽  
Han-Gyu Choi ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Cell Differentiation ◽  
Prostaglandin E2 ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Bacterial Load ◽  
Cell Responses ◽  
Ep4 Receptor ◽  
Th17 Cell Differentiation

Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.

Sign in / Sign up

Export Citation Format

Share Document