Implication des facteurs nutritionnels et du stress oxydant dans la régulation de l'expression génique au cours du vieillissement chez la souris

Le stress oxydant (SO) est impliqué dans le processus du vieillissement. Pour comprendre le rôle des facteurs nutritionnels sur le SO, nous étudions l'effet d'une alimentation standard, restrictive (RC), cafeteria (CD) et d'un SO chronique par le paraquat (PQ) sur des souris mâles C57BL6J au cours du vieillissement. Le statut antioxydant (SOD, GPX, Catalase et vitamines E, A) est estimé dans le sang, le foie et le cerveau. L'expression génique est suivie par cDNA array. Les performances cognitives sont évaluées par des tests comportementaux de mémoire. PQ et CD accélèrent la diminution liée à l'âge du SA et favorisent l'expression de gènes impliqués dans la prolifération et la différenciation cellulaire dans les différents tissus. Par contre, RC réprime la décroissance du SA et stimule l'expression des gènes de réparation et de renouvellement cellulaire.La diminution liée à l'âge des capacités d'apprentissage est augmentée par CD et PQ mais réprimée par RC comparé au témoin. Ces résultats montrent que l'interrelation entre le SO, le vieillissement tissulaire et cognitif qui peut être modulé par des facteurs nutritionnels.There is some evidence that diet and oxidative stress can modulate the ageing process. To assess the role of nutritional factors on oxidative stress in liver and brain during ageing, we separated mice C57BL6j male in 4 groups : a standard, restriction (RD) and cafeteria (CD) diets, a chronic oxidative stress by Paraquat (PQ). Blood, liver and brain antioxidant status (AS) was determined by vitamins A, E, superoxyde dismutase, gluthation peroxydase and catalase analysis. Gene expression was studied by using cDNA arrays. Cognitive performances were evaluated using behavioral tests. PQ and CD enhanced the effect of ageing on AS and learning capacity compared to controls. They activate expression of gene implicated in proliferation and differentiation in tissues. On contrary, RC decrease ageing effect on AS and acquisition capacity and increase expression of gene implicated in reparation and cell survival. These results suggested a relationship between OS, ageing tissue, cognitive performances that could be modified by nutritional factors.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Cultured Human Thymic-Derived Cells Display Medullary Thymic Epithelial Cell Phenotype and Functionality

International audienc

Prédisposition aux pathologies auto-immmunes

Les maladies auto-immunes sont un groupe d’environ 80 pathologies différentes affectant 5 à 8 % de la population. Elles sont dues à un dysfonctionnement du système immunitaire au niveau de la tolérance thymique. Le thymus est le site d’éducation des lymphocytes T. Cet apprentissage repose sur des interactions entre les lymphocytes T et les cellules épithéliales thymiques (CET) qui expriment les protéines spécifiques de tissus périphériques. Ce mécanisme complexe est appelé tolérance centrale. Les maladies auto-immunes présentent, pour la majorité d’entre elles, une forte prévalence féminine. La comparaison des transcriptomes thymiques de femmes et d’hommes met en évidence des différences d’expression des protéines spécifiques de tissus périphériques. Dans le thymus, l’expression de ces protéines est contrôlée par le modulateur de transcription AIRE (autoimmune regulator). Une analyse translationnelle de la relation entre le sexe, les hormones et AIRE, dans des modèles cellulaires humains et murins, montre qu’après la puberté, ce facteur est moins exprimé chez la femme que chez l’homme. Les estrogènes induisent une augmentation du nombre de sites de méthylation au niveau du promoteur de Aire réprimant ainsi son expression. À partir de la puberté, les femmes auraient une efficacité diminuée du processus de tolérance centrale, ce qui entraînerait un accroissement des cellules autoréactives et de leur susceptibilité aux maladies auto-immunes. Ces observations nous amènent à nous interroger sur les effets d’une exposition croissante aux perturbateurs endocriniens, molécules estrogen-like qui, en diminuant l’expression de AIRE, conduiraient à une augmentation de la fréquence des maladies auto-immunes

AIRE: a missing link to explain female susceptibility to autoimmune diseases

International audienc

IL-17, SKELETAL MUSCLE AND MYASTHENIA GRAVIS

International audienceIntroduction: Autoimmune myasthenia gravis (MG) is a rare neuromuscular disease due to auto-antibodies that target acetylcholine receptors (AChRs) located at the neuromuscular junction (Gilhus, Tzartos et al. 2019). The AChR + MG patients are affected by muscle weakness and fatigue. The autoantibodies are produced in the ectopic germinal centers found in the thymus, the disease effector organ. Previous data showed that the cytokine IL 17 contributes actively to the pathogenic events occurring in thymus of AChR + MG patients (Villegas, Bayer et al. 2019) (Zhao, Luo et al. 2021). We then aimed to study whether IL-17 participates also to the pathogenic events occurring in the tissue targeted by the autoantibodies, the skeletal muscle. Materials and methods: The mRNA expression level and the tissue localization of IL-17A were assessed respectively by quantitative RT-PCR and immunohistochemistry in the classical experimental MG mouse model (EAMG) Results: mRNA analysis showed a significant increased expression of IL-17A in skeletal muscle of EAMG mice compared to controls mice. Surprisingly, the IHC analysis of skeletal muscle (tibialis anterior) revealed that IL-17 staining is located intra muscle fibers. In addition, the number of IL-17 positive fibers in the TA of EAMG mice, compared to control mice, is significantly increased. More, the analysis of IL-17A mRNA level in skeletal muscles of AChR + MG patients showed a similar increased expression compared to healthy control muscle biopsies. Conclusion: For the first time, we observed that skeletal muscles of EAMG mice and MG patients display an increased expression of the pro-inflammatory cytokine IL-17A. The role of IL-17 in the skeletal muscle is not so far clearly identified. Therefore, further investigations is required to understand the role and mechanism of action of IL-17 in the MG muscle

Development of a new experimental Myasthenia Gravis mouse model.

International audienc

An imbalance between regulatory T cells and T helper 17 cells in acetylcholine receptor-positive myasthenia gravis patients

International audienc

Balance between Estrogens and Proinflammatory Cytokines Regulates Chemokine Production Involved in Thymic Germinal Center Formation

International audienceThe early-onset form of Myasthenia Gravis (MG) is prevalent in women and associates with ectopic germinal centers (GCs) development and inflammation in the thymus. we aimed to investigate the contribution of estrogens in the molecular processes involved in thymic GCs formation. We examined expression of genes involved in anti-acetylcholine receptor (AChR) response in MG, MHC class II and α-AChR subunit as well as chemokines involved in GC development (CXCL13, CCL21and CXCL12). In resting conditions, estrogens have strong regulatory effects on thymic epithelial cells (TECs), inducing a decreased protein expression of the above molecules. In knockout mouse models for estrogen receptor or aromatase, we observed that perturbation in estrogen transduction pathway altered MHC Class II, α-AChR, and CXCL13 expression. However, in inflammatory conditions, estrogen effects were partially overwhelmed by pro-inflammatory cytokines. Interestingly, estrogens were able to control production of type I interferon and therefore play dual roles during inflammatory events. In conclusion, we showed that estrogens inhibited expression of α-AChR and HLA-DR in TECs, suggesting that estrogens may alter the tolerization process and favor environment for an autoimmune response. By contrast, under inflammatory conditions, estrogen effects depend upon strength of the partner molecules with which it is confronted to

Author Correction: Balance between Estrogens and Proinflammatory Cytokines Regulates Chemokine Production Involved in Thymic Germinal Center Formation

International audienc

Myasthenia Gravis: An Acquired Interferonopathy?

International audienceMyasthenia gravis (MG) is a rare autoimmune disease mediated by antibodies against components of the neuromuscular junction, particularly the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG patients. In early-onset AChR-MG and thymoma-associated MG, an interferon type I (IFN-I) signature is clearly detected in the thymus. The origin of this chronic IFN-I expression in the thymus is not yet defined. IFN-I subtypes are normally produced in response to viral infection. However, genetic diseases called interferonopathies are associated with an aberrant chronic production of IFN-I defined as sterile inflammation. Some systemic autoimmune diseases also share common features with interferonopathies. This review aims to analyze the pathogenic role of IFN-I in these diseases as compared to AChR-MG in order to determine if AChR-MG could be an acquired interferonopathy