Identification of galectins as novel inflammatory mediators

Abstract

The human neutrophils play important roles in the host defence against invading microorganisms. To eliminate bacteria or other invaders the neutrophils have to leave the bloodstream and cross the endothelium, migrate through the extracellular matrix towards the site of infection and phagocytose the prey to ultimately kill it. By activation of the enzyme complex NADPH-oxidase, the neutrophils produce toxic oxygen metabolites that have bactericidal effects when released into the phagosome, but are tissue destructive if released extracellularly. Galectins are a family of today 14 b-galactoside-binding lectins produced and secreted by a variety of cell types. Some galectins are produced by cells involved in inflammatory processes and the aim of this study was to investigate the interaction of galectin-1 and galectin-3 with human neutrophils with emphasis on activation of the NADPH-oxidase. Both galectin-1 and galectin-3 have the ability to activate the NADPH-oxidase in neutrophils, provided that the cells are primed. Here, priming was achieved either in vivo, by transmigration from the bloodstream and extravasation into the tissue or in vitro by pre-incubating the cells with bacterial lipopolysaccharides or the formylated tripeptide fMLF. Regardless of priming technique, the induced galectin responsiveness was due to mobilisation of receptor-containing intracellular granules to the plasma membrane and subsequent upregulation of galectin receptors on the cell surface. By correlating the mobilisation of granule markers with the ability of galectin-1 to activate the NADPH-oxidase in differently primed cells, the intracellular localisation of the activating receptors in resting cells could be determined to the secretory vesicle and gelatinase granules. This is to be compared to the galectin-3 receptors, which are localised to the gelatinase and specific granules. A novel priming agent employing the same mechanism was also defined. Desialylation of the neutrophil cell surface by Newcastle Disease Virus neuraminidase induced a signal for degranulation resulting in priming for galectins.Based on the above it is evident that the galectins confer pro-inflammatory activities. It is of outmost importance that we increase our understanding of galectin function to define possible points of attack for regulation of the inflammatory process in vivo.