Galectin-1 Deactivates Classically Activated Microglia and Protects from Inflammation-Induced Neurodegeneration

SummaryInflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS

Galectin-4 and sulfatides in apical membrane trafficking in enterocyte-like cells

We have previously reported that 1-benzyl-2-acetamido-2-deoxy-α-d-galactopyranoside (GalNAcα-O-bn), an inhibitor of glycosylation, perturbed apical biosynthetic trafficking in polarized HT-29 cells suggesting an involvement of a lectin-based mechanism. Here, we have identified galectin-4 as one of the major components of detergent-resistant membranes (DRMs) isolated from HT-29 5M12 cells. Galectin-4 was also found in post-Golgi carrier vesicles. The functional role of galectin-4 in polarized trafficking in HT-29 5M12 cells was studied by using a retrovirus-mediated RNA interference. In galectin-4–depleted HT-29 5M12 cells apical membrane markers accumulated intracellularly. In contrast, basolateral membrane markers were not affected. Moreover, galectin-4 depletion altered the DRM association characteristics of apical proteins. Sulfatides with long chain-hydroxylated fatty acids, which were also enriched in DRMs, were identified as high-affinity ligands for galectin-4. Together, our data propose that interaction between galectin-4 and sulfatides plays a functional role in the clustering of lipid rafts for apical delivery

Rôle de la glycosylation et de la galectine-4 dans l'adressage à la membrane apicale dans les cellules HT-29 5M12 de phénotype entérocytaire

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

The role of galectins in protein trafficking.

International audienceThe galectins, a family of lectins, modulate distinct cellular processes, such as cancer progression, immune response and cellular development, through their specific binding to extracellular or intracellular ligands. In the past few years, research has unravelled interactions of different galectins with lipids and glycoproteins in the outer milieu or in the secretory pathway of cells. Interestingly, these lectins do not possess a signalling sequence to enter the endoplasmic reticulum as a starting point for the classical secretory pathway. Instead they use a so-called non-classical mechanism for translocation across the plasma membrane and/or into the lumen of transport vesicles. Here, they stabilize transport platforms for apical trafficking or sort apical glycoproteins into specific vesicle populations. Modes of ligand interaction as well as the modulation of binding activities and trafficking pathways are discussed in this review

La galectine-3, invitée inattendue à la table des négociations entre réticulum endoplasmique et mitochondrie

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Designer substrates and devices for mechanobiology study

International audienceBoth biological and engineering approaches have contributed significantly to the recent advance in the field of mechanobiology. Collaborating with biologists, bio-engineers and materials scientists have employed the techniques stemming from the conventional semiconductor industry to rebuild cellular milieus that mimic critical aspects of in vivo conditions and elicit cell/tissue responses in vitro. Such reductionist approaches have help to unveil important mechanosensing mechanism in both cellular and tissue level, including stem cell differentiation and proliferation, tissue expansion, wound healing, and cancer metastasis. In this mini-review, we discuss various microfabrication methods that have been applied to generate specific properties and functions of designer substrates/devices, which disclose cell-microenvironment interactions and the underlying biological mechanisms. In brief, we emphasize on the studies of cell/tissue mechanical responses to substrate adhesiveness, stiffness, topography, and shear flow. Moreover, we comment on the new concepts of measurement and paradigms for investigations of biological mechanotransductions that are yet to emerge due to ongoing interdisciplinary efforts in the fields of mechanobiology and microengineering

In vivo examination of the cortical cytoskeleton in multiciliated cells using electron tomography.

International audienceMulticiliated cells are characterized by coordinated arrays of motile cilia. In the respiratory tract, the maintenance of this array is essential to ensure proper ciliary and mucus clearance. The establishment and the maintenance of the ciliary set are mediated by the correct positioning of basal bodies at the cell cortex. While microtubule and actin cytoskeletons have been reported to regulate basal body lattices, an understanding of their detailed organization was missing until recently. Here, we describe how electron tomography can highlight the arrangement of the cytoskeletal networks and their interplay with basal bodies in ciliated cells in their tissular environment. Thanks to this approach, information in fine detail on large parts of the cell, dense in organelles, is provided. In combination with other approaches, such as transgenic animal models, electron tomography constitutes a powerful technique giving an overview of tissues and cells concomitantly with acquisition of three-dimensional detail

Plasticity of the brush border - the yin and yang of intestinal homeostasis.

International audienceThe brush border on the apical surface of enterocytes is a highly specialized structure well-adapted for efficient digestion and nutrient transport, whilst at the same time providing a protective barrier for the intestinal mucosa. The brush border is constituted of a densely ordered array of microvilli, protrusions of the plasma membrane, which are supported by actin-based microfilaments and interacting proteins and anchored in an apical network of actomyosin and intermediate filaments, the so-called terminal web. The highly dynamic, specialized apical domain is both an essential partner for the gut microbiota and an efficient signalling platform that enables adaptation to physiological stimuli from the external and internal milieu. Nevertheless, genetic alterations or various pathological stresses, such as infection, inflammation, and mechanical or nutritional alterations, can jeopardize this equilibrium and compromise intestinal functions. Long-time neglected, the intestinal brush-border shall be enlightening again as the central actor of the complex but essential intestinal homeostasis. Here, we review the processes and components involved in brush border organization and discuss pathological mechanisms that can induce brush border defects and their physiological consequences