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 CD147 Is Essential for the Development of Psoriasis via the Induction of Th17 Cell Differentiation

2021 ◽  
Vol 23 (1) ◽  
pp. 177
Author(s):  
Aoi Okubo ◽  
Youhei Uchida ◽  
Yuko Higashi ◽  
Takuya Sato ◽  
Youichi Ogawa ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Transmembrane Protein ◽  
Immunoglobulin Superfamily ◽  
Monocarboxylate Transporters ◽  
Th17 Cell Differentiation

Th17 cells play an important role in psoriasis. The differentiation of naïve CD4+ T cells into Th17 cells depends on glycolysis as the energy source. CD147/basigin, an integral transmembrane protein belonging to the immunoglobulin superfamily, regulates glycolysis in association with monocarboxylate transporters (MCTs)-1 and -4 in cancer cells and T cells. We examined whether CD147/basigin is involved in the pathogenesis of psoriasis in humans and psoriasis-model mice. The serum level of CD147 was increased in patients with psoriasis, and the expression of CD147 and MCT-1 was elevated in their dermal CD4+ RORγt+ T cells. In vitro, the potential of naïve CD4+ T cells to differentiate into Th17 cells was abrogated in CD147−/− T cells. Imiquimod (IMQ)-induced psoriatic dermatitis was significantly milder in CD147−/− mice and bone marrow chimeric mice lacking CD147 in the hematopoietic cells of myeloid lineage. These findings demonstrate that CD147 is essential for the development of psoriasis via the induction of Th17 cell differentiation.

Mesenchymal Stromal Cells Derived From Bone Marrow of Chronic Lymphocytic Leukemia Patients Promote Th17 Cell Differentiation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2414-2414
Author(s):  
Wei Ding ◽  
Traci Sassoon ◽  
Justin Boysen ◽  
Neil E. Kay
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cytokine Production ◽  
Normal Subjects ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Cd4 Cells ◽  
Th17 Cell Differentiation

Abstract Abstract 2414 Background: Mesenchymal stromal cells (MSC) derived from normal subjects are known to have immunosuppressive capacity by virtue of inhibiting T- and B-cell activation. A novel subset of T cells, Th17, plays an important role in inflammation and autoimmunity. A recent report demonstrated that normal MSC ameliorates experimental autoimmune encephalomyelitis by inhibiting CD4+ Th17 cells in a chemokine ligand 2-dependent manner (J Immunol. 2009, 182: 5994). It remains unknown if MSC derived from leukemic or cancer patients play a role in Th17 cell differentiation. In particular this would be of interest to study in B-Chronic Lymphocytic Leukemia (CLL) where immunosuppression is evident even in early stage disease. Methods: MSC derived from bone marrow of CLL patients or normal subjects were expanded in vitro as previously described by us (Br J Haematol. 2009, 147:471). CD4+ cells positively selected from normal peripheral blood mononuclear cells were co-cultured with either CLL MSC or normal MSC at a ratio of 50:1 for 3 days with stimulation via CD3/CD28 beads, as well as interleukin-1β (IL-1β; 50 ng/ml). Then phorbol 12-myristate 13-acetate (50 ng/ml) and ionomycin (500 ng/ml) were introduced into the co-culture for 5 hrs in the presence of brefeldin A. Subsequently, cells were stained with CD4-phycoerythrin (PE) and IL-17-Alexa647 using intracellular flow to analyze the percent expression of IL-17 in CD4 + cells. Cytokine production from both CLL MSC and normal MSC as secreted into culture medium (CM) were tested using a commercial multiplex cytokine array (Invitrogen, CA). This array measures the level of 30 different cytokines. Results: Positively selected CD4+ cells from peripheral blood of normal donors contain minimal percentages of Th17 cells (range: 0.48–0.71%). IL-1β stimulation induced increased IL-17 expression (range: 1.05–1.12%). Co-culture of CLL MSC with CD4+ cells induced significantly increased IL-17 expression in the CD4+ T cells (range: 1.16–1.32%). The promoting effect of CLL MSC on these Th17 cells appeared to be mediated by direct contact since the CM of CLL MSC was not able to induce increased IL-17 expression (mean = 0.66%) to a similar level as direct co-culture. When IL-1b was used to stimulate Th17 cell differentiation from CD4+ cells, CLL MSC were able to further promote the level of Th17 cell differentiation (range: 2.01–2.63%), indicating synergistic function for CLL MSC with IL-1β. This latter finding again appeared to be more pronounced for CLL MSC as normal MSC with IL-1β was not able to promote Th17 cell differentiation to a similar degree. To further investigate the mechanism of CLL MSC on Th17 cell differentiation, we assessed the cytokine production for resting CLL MSC and normal MSC compared to cytokine production of CLL and normal MSC stimulated with IL-17. The data from multiplex cytokine arrays revealed that the cytokine profiles were not different between resting CLL and normal MSC; however, when MSC were stimulated with IL-17, there were significant differences between CLL and normal MSC in terms of IL-6 and MCP-1 production (IL-6, CLL vs. normal, 957.9 ± 98 vs. 554.2 ± 92.3 pg/ml, p = 0.01; MCP-1, CLL vs. normal, 787.7 ± 166.9 vs. 330.2 ± 116.5 pg/ml, p = 0.04, n = 7). Since both IL-6 and MCP-1 have been demonstrated to play important roles in Th17 differentiation, we are conducting further studies to dissect the mechanism of CLL MSC in the promotion of Th17 cell differentiation. Conclusions: These results indicate that MSC derived from CLL patients promotes Th17 cell differentiation in vitro, which is in contrast to the previous published suppressive role of normal MSC on Th17 cell differentiation. Recent findings have indeed demonstrated that CLL patients do have high percentage of Th17 cells (Cancer Res. 2009. 69: 5922) when compared to other lymphoproliferative diseases. Given this data we believe that CLL MSC are intrinsically different from normal MSC in terms of immune regulation and cytokine production. This may occur as a result of the bi-directional activation that we found to be present between MSC and CLL leukemic cells (Br. J Haematol. 2009. 147:471). In total, our findings demonstrated that the dynamic interactions between the CLL leukemic cells and MSC appear to influence the Th 17 cell levels. This is of biological and clinical interest in that Th17 cells have the potential to regulate the immune environment to favor tumor proliferation and progression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals PTEN drives Th17 cell differentiation by preventing IL-2 production

2017 ◽  
Vol 214 (11) ◽  
pp. 3381-3398 ◽  
Author(s):  
Hyeong Su Kim ◽  
Sung Woong Jang ◽  
Wonyong Lee ◽  
Kiwan Kim ◽  
Hyogon Sohn ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Cell Subset ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
Stat3 Phosphorylation ◽  
Pten Deletion ◽  
Key Factor ◽  
Phosphatase And Tensin Homologue

T helper 17 (Th17) cells are a CD4+ T cell subset that produces IL-17A to mediate inflammation and autoimmunity. IL-2 inhibits Th17 cell differentiation. However, the mechanism by which IL-2 is suppressed during Th17 cell differentiation remains unclear. Here, we show that phosphatase and tensin homologue (PTEN) is a key factor that regulates Th17 cell differentiation by suppressing IL-2 production. Th17-specific Pten deletion (Ptenfl/flIl17acre) impairs Th17 cell differentiation in vitro and ameliorated symptoms of experimental autoimmune encephalomyelitis (EAE), a model of Th17-mediated autoimmune disease. Mechanistically, Pten deficiency up-regulates IL-2 and phosphorylation of STAT5, but reduces STAT3 phosphorylation, thereby inhibiting Th17 cell differentiation. PTEN inhibitors block Th17 cell differentiation in vitro and in the EAE model. Thus, PTEN plays a key role in Th17 cell differentiation by blocking IL-2 expression.

scholarly journals IFN-γ promoted exosomes from mesenchymal stem cells to attenuate colitis via miR-125a and miR-125b

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Ruili Yang ◽  
Huaming Huang ◽  
Shengjie Cui ◽  
Yikun Zhou ◽  
Ting Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Activity Index ◽  
Therapeutic Effects ◽  
Th17 Cell Differentiation ◽  
Ifn Γ

Abstract Bone marrow mesenchymal stem cells (MSCs) have demonstrated therapeutic effects for colitis through immunomodulation and anti-inflammation. However, whether MSC-derived exosomes possessed the similar function remains unclear. In present study, exosomes were isolated from control and IFN-γ-primed MSCs and was verified by transmission electron microscope (TEM) and immunofluorescence staining. Administration of exosomes to mice significantly improved the disease activity index and histological score of colitis, and decreased the ratio of Th17 cells with elevated Treg cells ratio in mice colitis model. Exosomes from IFN-γ-primed MSCs showed superior therapeutic effects to colitis. Exosomes treatment inhibited Th17 differentiation in vitro, and exosomes from IFN-γ-primed MSCs showed higher inhibition efficacy. Mechanistically, exosomes treatment significantly decreased the expression of Stat3 and p-Stat3 to inhibit Th17 cells differentiation. IFN-γ pretreatment increased the level of miR-125a and miR-125b of exosomes, which directly targeted on Stat3, to repress Th17 cell differentiation. Moreover, combination of miR-125a and miR-125b agmior infusion also showed therapeutic effects for colitis, accompanied by decreased Th17 cell ratio. Collectively, this study demonstrates that IFN-γ treatment promoted exosomes from MSCs to attenuate colitis through increasing the level of miR-125a and miR-125b, which binding on 3′-UTR of Stat3 to repress Th17 cell differentiation. This study provides a new approach of exocytosis on the treatment of colitis.

Hydroxychloroquine Inhibits the Differentiation of Th17 Cells in Systemic Lupus Erythematosus

2018 ◽  
Vol 45 (6) ◽  
pp. 818-826 ◽  
Author(s):  
Ji Yang ◽  
Xue Yang ◽  
Jie Yang ◽  
Ming Li
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Lupus Erythematosus ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Systemic Lupus ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Th17 Cell Differentiation

Objective.Hydroxychloroquine (HCQ) is a commonly used medicine for the treatment of systemic lupus erythematosus (SLE), and Th17 cells are closely related to the pathogenesis of SLE. However, the role and mechanism of HCQ on Th17 cell differentiation in SLE is not clearly understood. Here, we investigate the effect of HCQ on Th17 cell differentiation bothin vitroand in patients with SLE.Methods.Twenty-five patients with SLE were divided into 2 treatment groups: prednisone alone and HCQ plus prednisone. Interleukin 17 (IL-17) expression was analyzed by ELISA and real-time (RT)-PCR. Th17 were measured in patients with SLE by flow cytometry before and after HCQ treatment.In vitro, naive T cells were cultured in Th17-inducing conditions with or without HCQ. Cell differentiation and IL-17 expression were analyzed. Finally, transcriptome sequencing identified differential gene expression between naive T cells and induced Th17 cells.Results.In patients, HCQ plus prednisone treatment inhibited IL-17 production, gene expression, and Th17 cell differentiation.In vitro, HCQ inhibited Th17 cell proliferation and differentiation, as well as IL-17 production. Five microRNA were significantly different in Th17 cells compared with naive T cells, and HCQ treatment reversed this effect.In vivo, microRNA-590 (miR-590) was verified and was significantly decreased in Th17 cells, compared with naive T cells from lupus-prone mice. Moreover, miR-590 was increased in patients treated with HCQ plus prednisone.Conclusion.HCQ inhibited Th17 cell differentiation and IL-17 production bothin vitroand in patients with SLE. Our study provides additional evidence for HCQ as a treatment for SLE.

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 Soufeng sanjie formula alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Di Hua ◽  
Jie Yang ◽  
Qinghai Meng ◽  
Yuanyuan Ling ◽  
Qin Wei ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Lymph Nodes ◽  
Inflammatory Cytokines ◽  
Th17 Cell ◽  
Collagen Induced Arthritis ◽  
Expression Levels ◽  
Th17 Cell Differentiation ◽  
Spleen And Lymph Nodes ◽  
Seed Coats

Abstract Background Rheumatoid arthritis (RA) is a chronic autoimmune disease. Soufeng sanjie formula (SF), which is composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch), scorpion (dried body of Buthus martensii Karsch), astragali radix (dried root of Astragalus membranaceus (Fisch.) Bge), and black soybean seed coats (seed coats of Glycine max (L.) Merr), is a traditional Chinese prescription for treating RA. However, the mechanism of SF in treating RA remains unclear. This study was aim to investigate the anti-arthritic effects of SF in a collagen-induced arthritis (CIA) mouse model and explore the mechanism by which SF alleviates arthritis in CIA mice. Methods For in vivo studies, female DBA/1J mice were used to establish the CIA model, and either SF (183 or 550 mg/kg/day) or methotrexate (MTX, 920 mg/kg, twice/week) was orally administered to the mice from the day of arthritis onset. After administration for 30 days, degree of ankle joint destruction and serum levels of IgG and inflammatory cytokines were determined. The balance of Th17/Treg cells in the spleen and lymph nodes was analyzed using flow cytometry. Moreover, the expression levels of retinoic acid receptor-related orphan nuclear receptor (ROR) γt and phosphorylated STAT3 (pSTAT3, Tyr705) in the spleen were detected by immunohistochemistry. Furthermore, the effect of SF on Th17 cells differentiation in vitro was investigated in CD4+ T cells under Th17 polarization conditions. Results SF decreased the arthritis score, ameliorated paw swelling, and reduced cartilage loss in the joint of CIA mice. In addition, SF decreased the levels of bovine collagen-specific IgG in sera of CIA mice. SF decreased the levels of inflammatory cytokines (TNF-α, IL-6, and IL-17A) and increased the level of IL-10 both in the sera and the joint of CIA mice. Moreover, SF treatment rebalanced the Th17/Treg ratio in the spleen and lymph nodes of CIA mice. SF also reduced the expression levels of ROR γt and pSTAT3 (Tyr705) in the spleen of CIA mice. In vitro, SF treatment reduced Th17 cell generation and IL-17A production and inhibited the expression of RORγt, IRF4, IL-17A, and pSTAT3 (Tyr705) under Th17 polarization conditions. Conclusions Our results suggest that SF exhibits anti-arthritic effects and restores Th17/Treg homeostasis in CIA mice by inhibiting Th17 cell differentiation.

A1.7 The regulation of human in vitro TH17 cell differentiation

2015 ◽  
Vol 74 (Suppl 1) ◽  
pp. A3.1-A3
Author(s):  
E Baricza ◽  
E Lajkó ◽  
L Kőhidai ◽  
B Molnár-Érsek ◽  
N Marton ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cell Differentiation

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.

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