The glycocalyx is a layer of glycoconjugates found on the surface of both host cells and microorganisms. Information presented on some of the glycans on glycoconjugates is recognized by mammalian glycan-binding proteins, lectins, and these interactions modulate various physiological processes, including host innate immune responses. Lectins and host glycoconjugates are synthesized in the same secretory pathway. One notable exception is a family of soluble β-galactoside-binding lectins, galectins, which are synthesized and accumulated in the cytosol and thereby segregated from their glycan ligands. In cases where pathogenic infection persists and tissue injury occurs, galectins are passively released from injured cells. In addition, galectins are actively secreted through unconventional secretory pathways by inflammation-activated or differentiating cells. Thus, extracellular emergence of galectins is associated with the presence of pathogenic hazards. Evidence from a series of studies suggests that galectins exert multiple immunological effects. Extracellular galectin-3 acts as a damage-associated molecular pattern (DAMP) and adhesion molecule for neutrophils in lungs to initiate a proinflammatory response and to mediate rapid neutrophil migration in lungs infected with pathogenic microorganisms. In this review, the roles of galectin-3 in initial innate immune responses and resolution are discussed together with a historical overview of research on galectins in the secretory pathway and innate immunology.
A. Galectins Accumulate in the Cytosol: Distinct Segregation from Glycan LigandsIn mammalian cells, the majority of glycans, i.e., oligosaccharides and polysaccharides, are covalently linked to either proteins Galectins are soluble, non-glycosylated lectins defined by a conserved carbohydrate recognition domain (CRD) that shows affinity for β-galactoside, especially glycans containing a number of lactosamine residues (Galβ1-4GlcNAc) (2-4). Detailed information on the carbohydrate binding specificity of galectins has been provided in the review by the group of Hirabayashi in the TIGG special issue 'Galectins updated' (5). In humans, 11 galectins have been identified to date (2). These proteins exhibit structural differences in the presentation of CRD (Fig. 1A). Some contain one CRD (prototype) and exist as either monomers or dimers while others (tandem repeats) contain two CRDs connected by a short linker region. Galectin-3 uniquely occurs as a chimeric protein with one CRD at the C-terminus and an additional non-CRD domain at the N-terminus, which is involved in its oligomerization.Upon binding to its glycan ligands, the conformation of galectin-3 appears altered. Subsequently, galectin-3 molecules oligomerize through self-assembly of the non-CRD domains and become multivalent in glycan binding (Fig. 1B) (6-12). In addition to N-terminal-mediated oligomerization, CRD of galectin-3 selfassociates upon binding to its ligands, thereby contributing to positive cooperativity in the formation of multivalency ...
