Altered T cell plasticity favours Th17 cells in early arthritis

Rheumatology ◽  
2020 ◽  
Vol 59 (10) ◽  
pp. 2754-2763 ◽  
Author(s):  
Jan Leipe ◽  
Fausto Pirronello ◽  
Hendrik Schulze-Koops ◽  
Alla Skapenko
Keyword(s):  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Th2 Cells ◽  
Healthy Controls ◽  
Early Ra ◽  
Forkhead Box ◽  
Th Cell ◽  
Plastic Process

Abstract Objectives The predominance of differentiated Th17 cells has been implied as a key driver of autoimmune arthritis, including early RA. Because accumulating evidence suggests that Th cell differentiation is a plastic process, we investigated plasticity and underlying molecular mechanisms to address the shift towards the Th17 phenotype in early RA. Methods A cohort of 61 patients with early, active, untreated RA and 45 age- and sex-matched healthy controls were studied. Viable in vitro- and in vivo-generated Th1, Th2 and Th17 cells were FACS-sorted and transdifferentiated under Th1-, Th2- or Th17-inducing conditions. The cytokine Th profile of the transdifferentiated cells was assessed by flow cytometry. Th cell-associated cytokine and transcription factor gene loci were analysed by chromatin immunoprecipitation assay and their expression by quantitative real-time PCR. Results In vitro-generated Th cells showed substantial plasticity, which was similar between RA and healthy controls, whereas in vivo-derived Th1 and Th2 cells from RA patients demonstrated an enhanced plasticity towards IL-17-expressing phenotypes compared with healthy controls. Further, in vivo-generated Th17 cells from RA patients showed a resistance to transdifferentiate into Th1 or Th2 cells. The serum/glucocorticoid-regulated kinase 1–forkhead box protein O1–IL-23 receptor (SGK1–FOXO1–IL-23R) axis together with increased RORC expression was associated with the predominant Th17 phenotype in early RA. Conclusions Our data indicate that in vivo-originated Th subsets are prone to Th17 cell transdifferentiation in early RA, while Th17 cells are resistant to changes in their phenotype. Together, the data imply that an altered plasticity contributes to the Th17 shift in early RA.

scholarly journals A Signal Transducer and Activator of  Transcription (Stat)4-independent Pathway for the Development of  T Helper Type 1 Cells

1998 ◽  
Vol 188 (6) ◽  
pp. 1191-1196 ◽  
Author(s):  
Mark H. Kaplan ◽  
Andrea L. Wurster ◽  
Michael J. Grusby
Keyword(s):  
Delayed Type Hypersensitivity ◽  
Th2 Cells ◽  
Signal Transducer ◽  
T Helper ◽  
Th1 Cell ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The differentiation of T helper (Th) cells is regulated by members of the signal transducer and activator of transcription (STAT) family of signaling molecules. We have generated mice lacking both Stat4 and Stat6 to examine the ability of Th cells to develop in the absence of these two transcription factors. Stat4, Stat6−/− lymphocytes fail to differentiate into interleukin (IL)-4–secreting Th2 cells. However, in contrast to Stat4−/− lymphocytes, T cells from Stat4, Stat6−/− mice produce significant amounts of interferon (IFN)-γ when activated in vitro. Although Stat4, Stat6−/− lymphocytes produce less IFN-γ than IL-12–stimulated control lymphocytes, equivalent numbers of IFN-γ–secreting cells can be generated from cultures of Stat4, Stat6−/− lymphocytes activated under neutral conditions and control lymphocytes activated under Th1 cell–promoting conditions. Moreover, Stat4, Stat6−/− mice are able to mount an in vivo Th1 cell–mediated delayed-type hypersensitivity response. These results support a model of Th cell differentiation in which the generation of Th2 cells requires Stat6, whereas a Stat4-independent pathway exists for the development of Th1 cells.

scholarly journals IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN

2018 ◽  
Vol 29 (7) ◽  
pp. 1825-1837 ◽  
Author(s):  
Paul Diefenhardt ◽  
Anna Nosko ◽  
Malte A. Kluger ◽  
Johannes V. Richter ◽  
Claudia Wegscheid ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Th17 Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Receptor Signaling ◽  
Dendritic Cell Activation ◽  
Fluorescent Reporter

Background Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear.Methods We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum–induced nephritis as a model of crescentic GN. Immune responses and Treg phenotypes were extensively analyzed.Results Compared with controls, mice with IL-10Ra−/− Tregs showed a spontaneously overshooting Th17 immune response. This hyper-Th17 phenotype was further boosted during GN and associated with aggravated renal injury. Notably, abrogation of IL-10Ra signaling in Tregs increased dendritic cell activation and production of Th17-inducing cytokines. In contrast, Treg trafficking and expression of chemokine receptor CCR6 remained unaffected, indicating mechanisms of Th17 control, differing from those of previously identified CCR6+ Treg17 cells. Indeed, the capacity for direct in vitro suppression of Th17 responses by IL-10Ra−/− Tregs was significantly impaired. As underlying pathology, analyses conducted in vitro and in vivo using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra−/− Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra−/− T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN.Conclusions IL-10R engagement optimizes Treg-mediated suppression of Th17 immunity. We hypothesize a feed-forward loop, in which IL-10Ra signaling reinforces IL-10 secretion by Tregs which potently controls Th17 development via direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN.

scholarly journals Involvement of miR-214-3p/FOXM1 axis during the progression of psoriasis

2021 ◽  
Author(s):  
Jin Zhao ◽  
Fei Wang ◽  
Qingjun Tian ◽  
Jing Dong ◽  
Liuqing Chen ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cyclin B1 ◽  
Mrna Degradation ◽  
Hacat Cells ◽  
Forkhead Box ◽  
Forkhead Box M1 ◽  
Non Coding Rnas ◽  
Novel Target

Abstract Psoriasis is a common, chronic, and relapsing skin disease characterized by hyperproliferation of keratinocytes and apoptosis delay. However, the molecular mechanisms underlying the progression of psoriasis remain elusive. MicroRNAs (miRNAs) are single-stranded, small non-coding RNAs that play a crucial role in the development of psoriasis by promoting targeted mRNA degradation or translational inhibition. Here, we report that miR-214-3p, one of the down-regulated miRNAs identified in the skin of psoriatic patients and imiquimod (IMQ)-induced mouse models, can negatively regulate the expression of forkhead box M1 (FOXM1). miR-214-3p inhibition leads to hyperproliferation and increased apoptosis of keratinocytes in vitro. Moreover, we show that miR-214-3p inhibition causes an arrest of the cell cycle at the S stage by elevating the expression of NEK2, KIF20A, CENP-A, CENP-F, Cyclin B1, and by reducing the expression of Cyclin D1 in HaCaT cells. In vivo, administration of miR-214-3p attenuates the psoriasis-like phenotype in IMQ-induced mice. Collectively, our results suggest that miR-214-3p/FOXM1 axis in keratinocytes could be a novel target in the treatment of psoriasis.

scholarly journals The Review of in Vitro and in Vivo Studies over the Glycyrrhizic Acid as Natural Remedy Option for Treatment of Allergic Asthma

2019 ◽  
Author(s):  
Saloomeh Fouladi ◽  
Mohsen Masjedi ◽  
Mazdak Ganjalikhani Hakemi ◽  
Nahid Eskandari
Keyword(s):  
Allergic Asthma ◽  
Molecular Mechanisms ◽  
Glycyrrhizic Acid ◽  
Data Bank ◽  
In Vivo Studies ◽  
Th2 Cells ◽  
Antitumor Effects ◽  
Anti Inflammatory

Allergic asthma is the most common type of allergy which have become increasingly prevalent in all around the world. Airway eosinophilic inflammation is a major feature of allergic asthma. Glycyrrhiza uralensis (licorice) is one of the regular herbs in traditional Chinese medicine (TCM) as it has many effects on the immune system such as anti-inflammatory and immune regulatory activity; antiviral and antitumor effects. This review focuses on the "licorice” components, mainly glycyrrhizic acid (GA) and derivatives structure that evaluate its effects on the allergic asthma. We performed searching articles in Pubmed, Web of Science, and Scopus data bank from 1990 to 2017. The search syntax were: "glycyrrhizin" OR " glycyrrhizic acid" OR " glycyrrhizinic acid" OR" glycyrrhiza glabra" OR " liquorice root" OR "G. glabra" OR "glycyrrhizic Acid" AND "allergic asthma" OR "bronchial asthma" OR "asthma, bronchial" OR "airway hyper-responsiveness" OR "airway inflammation".   Several molecular mechanisms and inflammatory mediators may possibly be responsible for efficacy of glycyrrhizin. Some in vitro studies indicated to the fact that possible mechanisms of anti-inflammatory effects could be through reduction of pro-inflammatory mediator's synthesis that motivates eosinophil, basophils and mast cells to release cytokines for the differentiation of T helper cells into Th2 cells to secrete interleukins. Furthermore, some transcription factors such as NF-κB, STAT6 and HDAC2 go between modulations of anti-asthmatic effects. The last but not the least it can be said that glycyrrhizin is potentially a good herbal drug with the lower most adverse effects for asthma treatment.

scholarly journals Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides

2006 ◽  
Vol 203 (10) ◽  
pp. 2271-2279 ◽  
Author(s):  
Spencer C. Liang ◽  
Xiang-Yang Tan ◽  
Deborah P. Luxenberg ◽  
Riyez Karim ◽  
Kyriaki Dunussi-Joannopoulos ◽  
...  
Keyword(s):  
Antimicrobial Peptides ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Th2 Cells ◽  
T Helper ◽  
Distinct Lineage ◽  
Th 1

Th17 cells are a distinct lineage of effector CD4+ T cells characterized by their production of interleukin (IL)-17. We demonstrate that Th17 cells also expressed IL-22, an IL-10 family member, at substantially higher amounts than T helper (Th)1 or Th2 cells. Similar to IL-17A, IL-22 expression was initiated by transforming growth factor β signaling in the context of IL-6 and other proinflammatory cytokines. The subsequent expansion of IL-22–producing cells was dependent on IL-23. We further demonstrate that IL-22 was coexpressed in vitro and in vivo with both IL-17A and IL-17F. To study a functional relationship among these cytokines, we examined the expression of antimicrobial peptides by primary keratinocytes treated with combinations of IL-22, IL-17A, and IL-17F. IL-22 in conjunction with IL-17A or IL-17F synergistically induced the expression of β-defensin 2 and S100A9 and additively enhanced the expression of S100A7 and S100A8. Collectively, we have identified IL-22 as a new cytokine expressed by Th17 cells that synergizes with IL-17A or IL-17F to regulate genes associated with skin innate immunity.

scholarly journals NK cell receptor NKG2D enforces proinflammatory features and pathogenicity of Th1 and Th17 cells

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
Marina Babic ◽  
Christoforos Dimitropoulos ◽  
Quirin Hammer ◽  
Christina Stehle ◽  
Frederik Heinrich ◽  
...  
Keyword(s):  
T Cells ◽  
Th17 Cells ◽  
Nk Cell ◽  
Inflammatory Diseases ◽  
Cell Receptor ◽  
Cell Mediated Immunity ◽  
Signature Genes ◽  
Th Cell

NKG2D is a danger sensor expressed on different subsets of innate and adaptive lymphocytes. Despite its established role as a potent activator of the immune system, NKG2D-driven regulation of CD4+ T helper (Th) cell–mediated immunity remains unclear. In this study, we demonstrate that NKG2D modulates Th1 and proinflammatory T-bet+ Th17 cell effector functions in vitro and in vivo. In particular, NKG2D promotes higher production of proinflammatory cytokines by Th1 and T-bet+ Th17 cells and reinforces their transcription of type 1 signature genes, including Tbx21. Conditional deletion of NKG2D in T cells impairs the ability of antigen-specific CD4+ T cells to promote inflammation in vivo during antigen-induced arthritis and experimental autoimmune encephalomyelitis, indicating that NKG2D is an important target for the amelioration of Th1- and Th17-mediated chronic inflammatory diseases.

scholarly journals Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells

2011 ◽  
Vol 208 (11) ◽  
pp. 2291-2303 ◽  
Author(s):  
Kamran Ghoreschi ◽  
Jürgen Brück ◽  
Christina Kellerer ◽  
Caishu Deng ◽  
Haiyan Peng ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dendritic Cells ◽  
Autoimmune Diseases ◽  
Th2 Cells ◽  
Type Ii ◽  
Autoimmune Encephalomyelitis ◽  
Th Cell ◽  
Experimental Autoimmune

Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4–producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4–producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.

scholarly journals Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells

2002 ◽  
Vol 196 (7) ◽  
pp. 969-977 ◽  
Author(s):  
Andrea L. Wurster ◽  
Vikki L. Rodgers ◽  
Abhay R. Satoskar ◽  
Matthew J. Whitters ◽  
Deborah A. Young ◽  
...  
Keyword(s):  
Interferon Γ ◽  
Th2 Cells ◽  
Th1 Cells ◽  
T Helper ◽  
Th2 Response ◽  
Th Cells ◽  
Th Cell ◽  
Ifn Γ

The cytokine potential of developing T helper (Th) cells is directly shaped both positively and negatively by the cytokines expressed by the effector Th cell subsets. Here we find that the recently identified cytokine, interleukin (IL)-21, is preferentially expressed by Th2 cells when compared with Th1 cells generated in vitro and in vivo. Exposure of naive Th precursors to IL-21 inhibits interferon (IFN)-γ production from developing Th1 cells. The repression of IFN-γ production is specific in that the expression of other Th1 and Th2 cytokines is unaffected. IL-21 decreases the IL-12 responsiveness of developing Th cells by specifically reducing both signal transducer and activator of transcription 4 protein and mRNA expression. These results suggest that Th2 cell-derived IL-21 regulates the development of IFN-γ–producing Th1 cells which could serve to amplify a Th2 response.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

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