scholarly journals Complement promotes the development of inflammatory T-helper 17 cells through synergistic interaction with Toll-like receptor signaling and interleukin-6 production

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1005-1015 ◽  
Author(s):  
Chongyun Fang ◽  
Xinhua Zhang ◽  
Takashi Miwa ◽  
Wen-Chao Song
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Transfer Model ◽  
T Helper ◽  
T Helper 17 ◽  
C5a Receptor ◽  
Serum Factors ◽  
Th17 Cell Differentiation

Toll-like receptors (TLRs) and complement are 2 major components of innate immunity that provide a first-line host defense and shape the adaptive immune responses. We show here that coincidental activation of complement and several TLRs in mice led to the synergistic production of serum factors that promoted T-helper cell 17 (Th17) differentiation from anti-CD3/CD28 or antigen-stimulated T cells. Although multiple TLR-triggered cytokines were regulated by complement, Th17 cell–promoting activity in the serum was correlated with interleukin (IL)–6 induction, and antibody neutralization of IL-6 abrogated the complement effect. By using both in vitro and in vivo approaches, we examined in more detail the mechanism and physiologic implication of complement/TLR4 interaction on Th17-cell differentiation. We found that the complement effect required C5a receptor, was evident at physiologically relevant levels of C5a, and could be demonstrated in cultured peritoneal macrophages as well as in the setting of antigen immunization. Importantly, despite an inhibitory effect of complement on IL-23 production, complement-promoted Th17 cells were functionally competent in causing autoimmunity in an adoptive transfer model of experimental autoimmune encephalomyelitis. Collectively, these data establish a link between complement/TLR interaction and Th17-cell differentiation and provide new insight into the mechanism of action of complement in autoimmunity.

scholarly journals RORα enforces stability of the T-helper-17 cell effector program

2020 ◽  
Author(s):  
June-Yong Lee ◽  
Jason A. Hall ◽  
Maria Pokrovskii ◽  
Lina Kroehling ◽  
Lin Wu ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Helper ◽  
T Helper 17 ◽  
Enhancer Element ◽  
Peripheral Tissues ◽  
Th17 Cell Differentiation

SummaryT helper 17 (Th17) cells regulate mucosal barrier defenses, but also promote multiple autoinflammatory diseases. Although many molecular determinants of Th17 cell differentiation have been described, the transcriptional programs that sustain Th17 cells in vivo remain obscure. The transcription factor RORγt is critical for Th17 cell differentiation, but a distinct role of the closely-related RORα, which is co-expressed in Th17 cells, is not known. Here we demonstrate that, although dispensable for Th17 cell differentiation, RORα governs optimal Th17 responses in peripheral tissues. Thus, the absence of RORα in T cells led to significant reductions in both RORγt expression and effector function amongst Th17 cells, due to need for cooperative RORα and RORγt binding to a newly-identified Rorc enhancer element that is essential for Th17 lineage maintenance in vivo. Altogether, these data point to a non-redundant role of RORα in Th17 lineage maintenance via reinforcement of the RORγt transcriptional program.

scholarly journals BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice

2017 ◽  
Vol 114 (11) ◽  
pp. 2952-2957 ◽  
Author(s):  
Kalung Cheung ◽  
Geming Lu ◽  
Rajal Sharma ◽  
Adam Vincek ◽  
Ruihua Zhang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Rna Polymerase Ii ◽  
Th17 Cell ◽  
Therapeutic Potential ◽  
Th2 Cells ◽  
Immune Functions ◽  
T Helper ◽  
T Helper 17 ◽  
Inflammatory Disorders ◽  
Th17 Cell Differentiation

T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4+ T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. We further show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowel diseases.

scholarly journals Tumor exosome promotes Th17 cell differentiation by transmitting the lncRNA CRNDE-h in colorectal cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Junfeng Sun ◽  
Haowei Jia ◽  
Xingqi Bao ◽  
Yue Wu ◽  
Tianyu Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Cell Differentiation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
T Helper 17 ◽  
Th17 Cell Differentiation

AbstractThe T helper 17 (Th17) cells in tumor microenvironment play an important role in colorectal cancer (CRC) progression. This study investigated the mechanism of Th17 cell differentiation in CRC with a focus on the role of tumor exosome-transmitted long noncoding RNA (lncRNA). Exosomes were isolated from the CRC cells and serum of CRC patients. The role and mechanism of the lncRNA CRNDE-h transmitted by CRC exosomes in Th17 cell differentiation were assessed by using various molecular biological methods. The serum exosomal CRNDE-h level was positively correlated with the proportion of Th17 cells in the tumor-infiltrating T cells in CRC patients. CRC exosomes contained abundant CRNDE-h and transmitted them to CD4+ T cells to increase the Th17 cell proportion, RORγt expression, and IL-17 promoter activity. The underlying mechanism is that, CRNDE-h bound to the PPXY motif of RORγt and impeded the ubiquitination and degradation of RORγt by inhibiting its binding with the E3 ubiquitin ligase Itch. The in vivo experiments confirmed that the targeted silence of CRNDE-h in CD4+ T cells attenuated the CRC tumor growth in mice. The present findings demonstrated that the tumor exosome transmitted CRNDE-h promoted Th17 cell differentiation by inhibiting the Itch-mediated ubiquitination and degradation of RORγt in CRC, expanding our understanding of Th17 cell differentiation in CRC.

scholarly journals STAT3-mediated TH17 cell Differentiation was Related to the Carcinogenesis of Colitis Related Cancer

2020 ◽  
Author(s):  
Shiyong Lin ◽  
Qianwen Liu ◽  
Jing Wen ◽  
Kunhao Bai ◽  
Yandong Guo ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Inflammatory Diseases ◽  
Luciferase Assay ◽  
Transfer Model ◽  
Mice Model ◽  
T Helper 17 ◽  
Colon Tumorigenesis ◽  
Th17 Cell Differentiation ◽  
T Cell Transfer

Abstract Background: Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the miR-124 acts as a safeguard to inhibit the pro-inflammatory production and reparative regeneration.Methods: The expression levels of miR-124 and IL-17, IFN-γ were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). TH17 or TH1 cells were detected by flow cytometer, respectively. the binding of STAT3 to the promoter region of IL-17 gene was analyzed by Chip assay . miR-124 binding to the 3’UTR of STAT3 gene was detected by reported plasmid construction and luciferase assay. Furthermore, DSS-induced colitis mice model and T cell transfer model were used to confirm the function of miR-124 in vivo. The related gene expression was analyzed by ELISA and western blot experiments.Results: The results indicated that miR-124a deficiency leads to colon tumorigenesis after Citrobacter rodentium infection and AOM/DSS induced colon cancer murine model. In molecular mechanism, miR-124 targets STAT3 to suppress T helper 17 (TH17) cell differentiation and expansion, and keep TH17 polarization in colonic microenvironment.Conclusions: Our study highlights highlight the potential role of miR-124 in the control of immune responses and pathogenesis of inflammatory diseases.

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 miRNAs Alter T Helper 17 Cell Fate in the Pathogenesis of Autoimmune Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Junxia Huang ◽  
Xinzhi Xu ◽  
Ji Yang
Keyword(s):  
Immune Response ◽  
Cell Differentiation ◽  
Autoimmune Diseases ◽  
Cell Fate ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Helper ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
And Function

T helper 17 (Th17) cells are characterized by the secretion of the IL-17 cytokine and are essential for the immune response against bacterial and fungal infections. Despite the beneficial roles of Th17 cells, unrestrained IL-17 production can contribute to immunopathology and inflammatory autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Although these diverse outcomes are directed by the activation of Th17 cells, the regulation of Th17 cells is incompletely understood. The discovery that microRNAs (miRNAs) are involved in the regulation of Th17 cell differentiation and function has greatly improved our understanding of Th17 cells in immune response and disease. Here, we provide an overview of the biogenesis and function of miRNA and summarize the role of miRNAs in Th17 cell differentiation and function. Finally, we focus on recent advances in miRNA-mediated dysregulation of Th17 cell fate in autoimmune diseases.

scholarly journals Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes

2020 ◽  
Author(s):  
Teruyuki Sano ◽  
Takahiro Kageyama ◽  
Victoria Fang ◽  
Ranit Kedmi ◽  
Jhimmy Talbot ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Lymph Nodes ◽  
Lamina Propria ◽  
Th17 Cell ◽  
Mucosal Barrier ◽  
T Helper ◽  
Mesenteric Lymph Nodes ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
Draining Lymph Nodes

SummaryDifferentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here we show that intestine-draining mesenteric lymph nodes (MLN) are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their up-regulation of integrin β7. Stat3-dependent induction of RORγt, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFB-directed Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLN and accumulation of the cells in the lamina propria.

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.

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