Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination

Abstract Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences

Unexpected role of androgen signaling upon demyelination of the central nervous system in female mice : Identification of sex-dependent specificities

La sclérose en plaques (SEP) est la plus commune des maladies démyélinisantes du système nerveux central (SNC). Elle se caractérise par une succession d'épisodes inflammatoires en partie liés à une dérégulation du système immunitaire et ciblant les cellules synthétisant la myéline, les oligodendrocytes. Ces épisodes sont d'abord suivis de phases de rémission correspondant à la régénération spontanée de la myéline détruite, encore appelée remyélinisation. Cependant, au fur et à mesure de la progression de la pathologie, la remyélinisation échoue notamment en raison d'une modification de l'environnement lésionnel qui devient inadapté au processus de réparation. Cette pathologie chronique et neurodégénérative est à l'heure actuelle considérée comme la première cause de handicaps lourds d'origine non traumatique chez l'adulte jeune. Elle concerne 3 femmes pour 1 homme. Au cours des dernières décennies, de nombreuses molécules visant le système immunitaire ont été identifiées afin de réduire la fréquence des attaques et leur sévérité. Ces molécules sont donc efficaces dans les formes récurrentes-rémittentes, mais deviennent inefficaces quand la maladie progresse. Le défi thérapeutique actuel est par conséquent l'identification de molécules qui permettraient également de favoriser la régénération de la myéline. Le rôle des hormones sexuelles mâles ou androgènes dans les modèles animaux de démyélinisation du SNC a fait l'objet de nombreuses études montrant leurs propriétés immunomodulatrices, neuroprotectrices et remyélinisantes chez le mâle. Puisque les souris femelles et les femmes produisent aussi des androgènes - bien qu'à un niveau beaucoup plus faible que les animaux mâles ou les hommes - l'objectif de mon projet de thèse était de déterminer la contribution des androgènes aux processus de protection et de régénération impliqués dans un contexte de démyélinisation chez les animaux femelles. Dans des modèles immuns (EAE) et non-immuns (LPC) de démyélinisation du SNC, les effets des androgènes ont été analysés par des immunomarquages et la visualisation de l'ultrastructure des axones et de la myéline, par des approches de tri des cellules immunitaires périphériques présentes dans les organes lymphoïdes et infiltrées dans le SNC. Les données indiquent des activités remyélinisantes, anti-inflammatoires et neuroprotectrices majeures des androgènes chez la femelle comme précédemment observé chez le mâle avec néanmoins plusieurs spécificités. Par ailleurs, une analyse transcriptomique de la moelle épinière des animaux EAE nous a conduit à identifier des gènes dont l'expression est dérégulée de façon cohérente avec les données histologiques et fonctionnelles. Ce projet suggère que le maintien d'un taux physiologique d'androgènes doit être pris en considération chez les patientes atteintes de SEP.Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). The pathology is characterized by successive inflammatory insults, which are related to the dysregulation of the immune system and target the cells synthesizing myelin in the CNS, the oligodendrocytes. These insults are followed by steps of remission corresponding to the spontaneous regeneration of myelin, also called remyelination. However, when the disease progress, remyelination fails namely due to a lesion environment becoming inappropriate. The pathology characterized as chronic and neurodegenerative concerns 3 women for 1 men and is currently considered as the first cause of non traumatic disabilities in the young adults. During the last decades, a substantial number of molecules targeting the immune system has been identified in order to reduce the frequency and severity of the insults. These molecules are efficient on the relapsing-remitting form of the disease, but they become inefficient with disease progression. The current therapeutic challenge is the identification of molecules also able to boost the regeneration of myelin. The role of the male sexual hormones or androgens in models of CNS demyelination has been thoroughly investigated in males, which led to show their immunomodulatory, pro-myelinating and neuroprotective properties. Since females also produce androgens - though at a much lower level than males - the objective of my PhD project was to delineate the contribution of androgens to the protective and regenerative processes involved in the context of CNS demyelination in female mice. In immune (EAE) and non-immune (LPC) models of CNS demyelination, the effects of androgens have been analyzed via immunostaining experiments, visualization of myelin and axon ultrastructure, fluorescence-activated sorting of peripheral immune cells present in the lymphoid organs or infiltrated in the CNS. The data indicate major remyelinating, anti-inflammatory and neuroprotective activities of androgens in females as previously observed in males with however some specificities. Moreover, transcriptomic analysis of the spinal cord from EAE animals led us to identify profiles of deregulated genes tightly correlated with the histological and functional data. Altogether these results suggest that the administration of appropriate doses of androgens would deserve to be further considered in female patients presenting with multiple sclerosis

Astrocytes et microglies, des acteurs majeurs de la production de la myéline en conditions normales et pathologiques

International audienceMyelination is an essential process that consists of the ensheathment of axons by myelin. In the central nervous system (CNS), myelin is synthesized by oligodendrocytes. The proliferation, migration, and differentiation of oligodendrocyte precursor cells constitute a prerequisite before mature oligodendrocytes extend their processes around the axons and progressively generate a multilamellar lipidic sheath. Although myelination is predominately driven by oligodendrocytes, the other glial cells including astrocytes and microglia, also contribute to this process. The present review is an update of the most recent emerging mechanisms involving astrocyte and microglia in myelin production. The contribution of these cells will be first described during developmental myelination that occurs in the early postnatal period and is critical for the proper development of cognition and behavior. Then, we will report the novel findings regarding the beneficial or deleterious effects of astroglia and microglia, which respectively promote or impair the endogenous capacity of oligodendrocyte progenitor cells (OPCs) to induce spontaneous remyelination after myelin loss. Acute delineation of astrocyte and microglia activities and cross-talk should uncover the way towards novel therapeutic perspectives aimed at recovering proper myelination during development or at breaking down the barriers impeding the regeneration of the damaged myelin that occurs in CNS demyelinating diseases

La galectine-9 favorise la persistance du virus de l’hépatite C dans le foie

Cette année encore, dans le cadre du module d’enseignement « Physiopathologie de la signalisation » proposé par l’université Paris-sud, les étudiants du Master « Biologie Santé » de l’université Paris-Saclay se sont confrontés à l’écriture scientifique. Ils ont sélectionné 12 articles scientifiques récents dans le domaine de la signalisation cellulaire présentant des résultats originaux, via des approches expérimentales variées, sur des thèmes allant des interactions hôte-pathogène au métabolisme, en passant par la compétition cellulaire et le microbiote. Après un travail préparatoire réalisé avec l’équipe pédagogique, les étudiants, organisés en binômes/trinômes, ont ensuite rédigé, guidés par des chercheurs, une Nouvelle soulignant les résultats majeurs et l’originalité de l’article étudié. Ils ont beaucoup apprécié cette initiation à l’écriture d’articles scientifiques et, comme vous pourrez le lire, se sont investis dans ce travail avec enthousiasme 

Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis

International audienceMotor neurons and their axons reaching the skeletal muscle have long been considered as the best characterized targets of the degenerative process observed in amyotrophic lateral sclerosis (ALS). However, the involvement of glial cells was also more recently reported. Although oligodendrocytes have been underestimated for a longer time than other cells, they are presently considered as critically involved in axonal injury and also conversely constitute a target for the toxic effects of the degenerative neurons. In the present review, we highlight the recent advances regarding oligodendroglial cell involvement in the pathogenesis of ALS. First, we present the oligodendroglial cells, the process of myelination, and the tight relationship between axons and myelin. The histological abnormalities observed in ALS and animal models of the disease are described, including myelin defects and oligodendroglial accumulation of pathological protein aggregates. Then, we present data that establish the existence of dysfunctional and degenerating oligodendroglial cells, the chain of events resulting in oligodendrocyte degeneration, and the most recent molecular mechanisms supporting oligodendrocyte death and dysfunction. Finally, we review the arguments in support of the primary versus secondary involvement of oligodendrocytes in the disease and discuss the therapeutic perspectives related to oligodendrocyte implication in ALS pathogenesis

The Smoothened agonist SAG Modulates the Male and Female Peripheral Immune Systems Differently in an Immune Model of Central Nervous System Demyelination

Both Hedgehog and androgen signaling pathways are known to promote myelin regeneration in the central nervous system. Remarkably, the combined administration of agonists of each pathway revealed their functional cooperation towards higher regeneration in demyelination models in males. Since multiple sclerosis, the most common demyelinating disease, predominates in women, and androgen effects were reported to diverge according to sex, it seemed essential to assess the existence of such cooperation in females. Here, we developed an intranasal formulation containing the Hedgehog signaling agonist SAG, either alone or in combination with testosterone. We show that SAG promotes myelin regeneration and presumably a pro-regenerative phenotype of microglia, thus mimicking the effects previously observed in males. However, unlike in males, the combined molecules failed to cooperate in the demyelinated females, as shown by the level of functional improvement observed. Consistent with this observation, SAG administered in the absence of testosterone amplified peripheral inflammation by presumably activating NK cells and thus counteracting a testosterone-induced reduction in Th17 cells when the molecules were combined. Altogether, the data uncover a sex-dependent effect of the Hedgehog signaling agonist SAG on the peripheral innate immune system that conditions its ability to cooperate or not with androgens in the context of demyelination

Coopération fonctionnelle des voies de signalisation Hedgehog et des androgènes au cours de la myélinisation développementale et réparatrice

International audienceAbstract Hedgehog morphogens control fundamental cellular processes during tissue development and regeneration. In the central nervous system (CNS), Hedgehog signaling has been implicated in oligodendrocyte and myelin production, where it functions in a concerted manner with other pathways. Since androgen receptor (AR) plays a key role in establishing the sexual phenotype of myelin during development and is required for spontaneous myelin regeneration in the adult CNS, we hypothesized the existence of a possible coordination between Hedgehog and androgen signals in oligodendrocyte and myelin production. Here, we report complementary activities of both pathways during early postnatal oligodendrogenesis further revealing that persistent Hedgehog signaling activation impedes myelin production. The data also uncover prominent pro‐myelinating activity of testosterone and involvement of AR in the control of neural stem cell commitment toward the oligodendroglial lineage. In the context of CNS demyelination, we provide evidence for the functional cooperation of the pathways leading to acceleration of myelin regeneration that might be related to their respective role on microglial and astroglial responses, higher preservation of axonal integrity, lower neuroinflammation, and functional improvement of animals in an immune model of CNS demyelination. Strong decreases of deleterious cytokines in the CNS (GM‐CSF, TNF‐α, IL‐17A) and spleen (IL‐2, IFN‐γ) stand as unique features of the combined drugs while the potent therapeutic activity of testosterone on peripheral immune cells contributes to increase tolerogenic CD11c + dendritic cells, reduce the clonal expansion of conventional CD4 + T cells and increase CD4 + Foxp3 + regulatory T cells. Altogether, these data might open promising perspectives for demyelinating diseases

LINGO family receptors are differentially expressed in the mouse brain and form native multimeric complexes

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