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The transcription factor Nrf2 regulates oxidative stress responses. However, the specific function of Nrf2 in Tregs, the central regulators of immune homeostasis, is unclear. Here, we report an unexpected but important role of Nrf2 in Tregs. Nrf2 expression driven by Foxp3 specific deletion of Keap1 resulted in an autoinflammatory phenotype with enhanced effector T cell activation and immune cell infiltrates in the lung. While early postnatal death of mice with Foxp3 specific deletion of Keap1 was most probably due to ectopic Foxp3cre expression and subsequent Keap1 deletion in epithelial cells, bone marrow chimeras suggest that Nrf2 activation intrinsically in Tregs contributes to a loss of Treg cells and diminished peripheral tolerance. Moreover, Nrf2 activation was associated with a loss of Foxp3 expression, but an enhanced glucose uptake and mTOR activity in Tregs, thus mimicking a metabolic phenotype that is associated with impaired lineage stability and cell functioning. [ABSTRACT FROM AUTHOR]

Background: Allergic diseases and especially allergic asthma are widespread diseases with high prevalence in childhood, but also in adults. Acid sphingomyelinase (ASM) is a key regulator of the sphingolipid pathway. Previous studies defined the association of ASM with the pathogenesis of TH1‐directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in TH2‐regulated allergic bronchial asthma. Methods: To determine the role of Asm under baseline conditions, wild‐type (WT) and Asm−/− mice were ventilated with a flexiVent setup and bronchial hyperresponsiveness was determined using acetylcholine. Flow cytometry and cytokine measurements in bronchoalveolar lavage fluid and lung tissue were followed by in vitro TH2 differentiations with cells from WT and Asm−/− mice and blockade of Asm with amitriptyline. As proof of principle, we conducted an ovalbumin‐induced model of asthma in WT‐ and Asm−/− mice. Results: At baseline, Asm−/− mice showed better lung mechanics, but unaltered bronchial hyperresponsiveness. Higher numbers of Asm−/− T cells in bronchoalveolar lavage fluid released lower levels of IL‐4 and IL‐5, and these results were paralleled by decreased production of typical TH2 cytokines in Asm−/− T lymphocytes in vitro. This phenotype could be imitated by incubation of T cells with amitriptyline. In the ovalbumin asthma model, Asm−/− animals were protected from high disease activity and showed better lung functions and lower levels of eosinophils and TH2 cytokines. Conclusion: Asm deficiency could induce higher numbers of TH2 cells in the lung, but those cells release decreased TH2 cytokine levels. Hereby, Asm−/− animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE), an autoimmune disease, develops when immunologic self-tolerance fails. Treg cells are a subset of CD4+ T cells that maintain self-tolerance by suppressing autoreactive lymphocytes. Defects in Treg cells are therefore considered to be an aspect of SLE pathogenesis. Nevertheless, reports on the numbers and function of Treg cells in SLE are contradictory and the definitive role of Treg cells in SLE remains unclear. In this review, we summarize findings from murine models and ex vivo experiments, which provide insights into the mechanisms that result in the breakdown of tolerance. We also include recent findings about Treg-cell subsets and their markers in human SLE. The identification of unique markers to identify bona fide Treg cells, as well as therapies to reconstitute the balance between Treg cells and autoreactive T cells in SLE, are the future challenges for SLE research. [ABSTRACT FROM AUTHOR]

Objective Interleukin-6 (IL-6) signaling plays an important proinflammatory role, but this role is restricted by regulatory mechanisms that, for example, reduce the cell surface availability of the signal-transducing chain of the IL-6 receptor, gp130. The aim of this study was to determine whether the inflammatory environment in arthritic joints has an impact on monocytic gp130 surface expression and the extent to which regulatory processes in the synovial fluid (SF) can be reproduced in an in vitro model. Methods Flow cytometry and live cell imaging were used to measure the cell surface expression and internalization of gp130. STAT-3 phosphorylation was monitored by flow cytometry and Western blotting. Results In patients with juvenile idiopathic arthritis (JIA), levels of cell surface gp130 expression in SF monocytes were reduced compared to those in peripheral blood (PB) monocytes. These reduced levels were reproduced when PB monocytes from healthy donors were stimulated with SF, and this reduction was dependent on p38 MAPK. The induction of p38 by IL-1β in PB monocytes interfered with IL-6 signaling due to the reduced cell surface expression of gp130. Conclusion These results suggest that p38-mediated proinflammatory stimuli induce the down-regulation of gp130 on monocytes and thus restrict gp130-mediated signal transduction. This regulatory mechanism could be of relevance to processes in the inflamed joints of patients with JIA. [ABSTRACT FROM AUTHOR]

Abstract: MIF is a chemokine-like inflammatory mediator that triggers leukocyte recruitment by binding to CXCR2 and CXCR4. MIF also interacts with CD74/invariant chain, a single-pass membrane-receptor. We identified complexes between CD74 and CXCR2 with a role in leukocyte recruitment. It is unknown whether CD74 also binds to CXCR4. We demonstrate that CD74/CXCR4 complexes formed when CD74 was expressed with CXCR4 in HEK293 cells. Expression of CD74-variants lacking an ER-retention signal showed CD74/CXCR4 complexes at the cell surface. Importantly, endogenous CD74/CXCR4 complexes were isolated by co-immunoprecipitation from monocytes. Finally, MIF-stimulated CD74-dependent AKT activation was blocked by anti-CXCR4 and anti-CD74 antibodies and AMD3100, whereas CXCL12-stimulated AKT activation was not reduced by anti-CD74. Thus, CD74 forms functional complexes with CXCR4 that mediate MIF-specific signaling. Structured summary: MINT-7234512, MINT-7234528: CD74 (uniprotkb:P04233) physically interacts (MI:0915) with CXCR4 (uniprotkb:P61073) by anti tag coimmunoprecipitation (MI:0007) MINT-7234542: CD74 (uniprotkb:P04233) and CXCR4 (uniprotkb:P61073) physically interact (MI:0915) by anti bait coimmunoprecipitation (MI:0006) MINT-7234499: CXCR4 (uniprotkb:P61073) and CD74 (uniprotkb:P04233) colocalize (MI:0403) by fluorescence microscopy (MI:0416) [Copyright &y& Elsevier]

Background: Allergic diseases and especially allergic asthma are widespread diseases with high prevalence in childhood, but also in adults. Acid sphingomyelinase (ASM) is a key regulator of the sphingolipid pathway. Previous studies defined the association of ASM with the pathogenesis of T H 1-directed lung diseases like cystic fibrosis and acute lung injury. Here, we define the role of ASM in T H 2-regulated allergic bronchial asthma., Methods: To determine the role of Asm under baseline conditions, wild-type (WT) and Asm -/- mice were ventilated with a flexiVent setup and bronchial hyperresponsiveness was determined using acetylcholine. Flow cytometry and cytokine measurements in bronchoalveolar lavage fluid and lung tissue were followed by in vitro T H 2 differentiations with cells from WT and Asm -/- mice and blockade of Asm with amitriptyline. As proof of principle, we conducted an ovalbumin-induced model of asthma in WT- and Asm -/-  mice., Results: At baseline, Asm -/- mice showed better lung mechanics, but unaltered bronchial hyperresponsiveness. Higher numbers of Asm -/- T cells in bronchoalveolar lavage fluid released lower levels of IL-4 and IL-5, and these results were paralleled by decreased production of typical T H 2 cytokines in Asm -/- T lymphocytes in vitro. This phenotype could be imitated by incubation of T cells with amitriptyline. In the ovalbumin asthma model, Asm -/- animals were protected from high disease activity and showed better lung functions and lower levels of eosinophils and T H 2 cytokines., Conclusion: Asm deficiency could induce higher numbers of T H 2 cells in the lung, but those cells release decreased T H 2 cytokine levels. Hereby, Asm -/- animals are protected from bronchial asthma, which possibly offers novel therapeutic strategies, for example, with ASM blockade., (© 2020 The Authors. Allergy published by John Wiley & Sons Ltd.)