Galectins as Novel Regulators of Immune Cell Homeostasis and Inflammation

RABINOVICH GA; TOSCANO MA; ILARREGUI JM; BAUM LG

Animal Lectins: A Functional View

CRC Press, Taylor and Francis Publishers

Lugar: London; Año: 2008; p. 395 - 414

 Galectins are a family of highly conserved glycan-binding proteins with affinity for ¥â-galactosidecontaining oligosaccharides. Since the discovery of discoidin-1 in the cellular slime mold Dictyostelium discoideum and electrolectin in the electric organ tissue of the electric eel, the family of galectins has received increasing attention. However it was only in the 1990s that experimental evidence emerged, illuminating a role for galectins in the regulation of physiological and pathological processes, particularly in the control of immune cell homeostasis and inflammation. Members of the galectin family are defined by a conserved carbohydrate recognition domain (CRD) with a canonical amino acid sequence and affinity for ¥â-galactosides. To date, 15 mammalian galectins have been identified, which can be subdivided into those that have one CRD (prototype) and those that have two CRDs in tandem (tandem-repeat type). In addition, galectin-3, a one-CRD galectin, is unique in that it contains unusual tandem repeats of short amino acid stretches fused onto the CRD (chimeratype). Many galectins bind carbohydrate moieties in a bivalent or multivalent manner. Some one-CRD galectins exist as dimers; two-CRD galectins have two carbohydrate-binding sites, and galectin-3 forms oligomers when it binds to multivalent carbohydrates. Galectin-mediated crosslinking of cell surface glycoconjugates can trigger a cascade of transmembrane signaling and modulate processes that include apoptosis, cytokine secretion, cell adhesion, and migration. Galectins can be found inside and outside cells, and have distinct functions in each location. Whether endogenously expressed, or rapidly internalized from the cell surface, galectins have been implicated in important intracellular functions such as pre-mRNA splicing, regulation of cell growth, cell cycle progression, and protein sorting. Although galectins do not contain signal peptides to direct them through the classical endoplasmic reticulum (ER)-Golgi apparatus secretory system, they can be secreted by other unorthodox secretory pathways. Once outside the cell, galectins bind to and cross-link multiple glycoconjugates found on the cell surface or in the extracellular matrix (ECM). Although most mammalian galectins bind preferentially to glycoconjugates containing the ubiquitous disaccharide N-acetyllactosamine [Gal¥â1-3GlcNAc or Gal¥â1-4GlcNAc], binding to individual lactosamine units is of relatively low affinity (Kd ¡­ 1 mM), and arrangement of lactosamine disaccharides in repeating chains (polylactosamine) increases binding avidity. Moreover, detailed structural analysis of the CRDs suggests subtle differences in carbohydrate-binding specificities of individual members of this family. Whether differences in saccharide specificity might be responsible for distinct biological effects in response to individual galectin binding still remains to be elucidated. Some galectins are distributed in a wide variety of tissues, whereas others have a more restricted localization. Within the immune system, galectins are found in activated macrophages, activated B cells, and activated T cells. Recent studies using gene expression arrays have indicated elevated expression of galectin-1 in CD4+ CD25+ regulatory T cells. The expression of galectins is modulated during the activation and differentiation of immune cells and may be significantly altered under several pathological conditions. Accumulating evidence has shown that galectins play a role in the initiation, activation, and resolution phases of innate and adaptive immune responses by promoting anti-inflammatory or proinflammatory effects. In this regard, it has been recently hypothesized that the same galectin may exert pro- or anti-inflammatory effects depending on multiple factors, such as the concentration reached in inflammatory foci, extracellular microenvironment, and the particular target cells impacted. It has been suggested that multivalency of individual members of the galectin family and their cross-linking properties might determine different biological responses by inducing aggregation of specific cell surface glycoreceptors, which in many cases, are associated with different signal transduction events. We will discuss here the anti-inflammatory and proinflammatory activities of different members of the galectin family on the physiology of different immune cell types. Finally, we will illustrate the impact of these immunoregulatory activities in the development and progression of chronic inflammatory disorders, autoimmunity, and cancer.