The Many Roles of Galectin-3, a Multifaceted Molecule, in Innate Immune Responses against Pathogens

Hindawi Mediators of Inflammation Volume 2017, Article ID 9247574, 10 pages https://doi.org/10.1155/2017/9247574 Review Article The Many Roles of Galectin-3, a Multifaceted Molecule, in Innate Immune Responses against Pathogens Laura Díaz-Alvarez and Enrique Ortega Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Ciudad de México, Mexico Correspondence should be addressed to Enrique Ortega; Received 3 February 2017; Revised 8 April 2017; Accepted 18 April 2017; Published 21 May 2017 Academic Editor: Jorge E. Vidal Copyright © 2017 Laura Díaz-Alvarez and Enrique Ortega. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Galectins are a group of evolutionarily conserved proteins with the ability to bind β-galactosides through characteristic carbohydrate-recognition domains (CRD). Galectin-3 is structurally unique among all galectins as it contains a C-terminal CRD linked to an N-terminal protein-binding domain, being the only chimeric galectin. Galectin-3 participates in many functions, both intra- and extracellularly. Among them, a prominent role for Galectin-3 in inflammation has been recognized. Galectin-3 has also been shown to directly bind to pathogens and to have various effects on the functions of the cells of the innate immune system. Thanks to these two properties, Galectin-3 participates in several ways in the innate immune response against invading pathogens. Galectin-3 has been proposed to function not only as a pattern-recognition receptor (PRR) but also as a dangerassociated molecular pattern (DAMP). In this review, we analyze the various roles that have been assigned to Galectin-3, both as a PRR and as a DAMP, in the context of immune responses against pathogenic microorganisms. Dedicated to the memory of Dr. Eduardo A García-Zepeda, a respected friend and colleague 1. Introduction Galectins are a group of evolutionarily conserved proteins present in vertebrates, invertebrates, and fungi [1]. They possess characteristic carbohydrate-recognition domains (CRD) of about 130 amino acids, through which they have the ability to bind β-galactosides (reviewed in [2]). So far, 15 mammalian galectins have been described. They can be structurally classified into three groups: prototype galectins (Galectins 1, 2, 5, 7, 10, 11, 13, 14, and 15) that have a single CRD; tandem galectins (Galectins 4, 6, 8, 9, and 12), with 2 distinct but homologous CRDs; and the chimera-type group, of which Galectin-3 (Gal-3) is the only member, with a C-terminal CRD and a large N-terminal (NT) protein-binding domain (reviewed in [3]). The human Gal-3 gene (LGALS3) spans 17 Kb and contains 6 exons and 5 introns. It has an open reading frame of 750 bp which translates into a protein of 250 aminoacids [4] with a Mr of approx. 30,000 [5, 6]. As aforementioned, Gal-3 has a unique structure among galectins. The C-terminal half, that is the CRD, is folded into a β-sandwich fashion with a tryptophan core and a noncanonical carbohydrate-binding site that mediates interaction with sugars such as Nacetyllactosamine (its preferential ligand), galactomannans, and polymannan [7, 8]. At the other end, the N-terminal region of about 120 residues contains an N-terminal stretch with two potential phosphorylation sites (residues 6 and 12) followed by a region containing several tandem repeats of short amino acid segments (P–G-A-Y-P–G). The glycineand proline-rich domain is involved in the ability of Gal-3 to oligomerize with other Gal-3 molecules or to establish protein-protein interactions with distinct proteins, like Alix from T cells and CD147 in keratinocytes [7, 9–12]. Gal-3 is widely distributed throughout the body; it can be found in a number of tissues such as the digestive and urogenital tracts, lungs, blood, kidneys, and heart. Gal-3 is highly expressed in myeloid cells (monocytes, macrophages, dendritic cells (DCs), neutrophils, etc.) and fibroblasts, as well 2 as in epithelial and endothelial cells [13–17]. At the cellular level, Gal-3 can be located in the cytoplasm, nucleus, and membranes, and it can also be found extracellularly after being released from cells following different stimuli, like LPS and interferon-γ, in both physiological and pathophysiological conditions [18, 19]. Several different functions have been attributed to intracellular Gal-3, including antiapoptotic activity and the regulation of mRNA splicing [20, 21], regulation of the FcεRI signaling pathway in mast cells [22], and modulation of the activation of RhoA and MLCK during cell invasion in hepatocellular carcinoma [22, 23]. For its part, extracellular Gal-3 (either membrane associated or free) also participates in a wide range of functions, including immunity against pathogens, and in both acute and chronic inflammation. Recent studies have demonstrated that Gal-3 can recognize microbial structures (pathogen-associated molecular patterns), that it has pro-inflammatory properties promoting the infiltration of neutrophils and other immune cells to the infected sites, and that it can also be released as a damageassociated molecular pattern [24]. In this review, we discuss several findings related to the participation of Gal-3 in immunity against pathogens, with special emphasis on its role in innate immunity. The roles of Gal-3 in different physiopathological settings, such as autoimmunity, cancer, and heart failure, have been recently reviewed [25–27]. 2. Secretion of Galectin-3 in Response to Infection After its synthesis, Gal-3 is stored in the cytoplasm, where it performs several functions, including some that require its entry into the nucleus. Upon different stimuli such as tissue damage or infection (see below), Gal-3 is either passively released from dying cells or actively secreted by activated cells. Once in the extracellular medium, secreted Gal-3 can act as a pattern-recognition receptor (PRR) and as an activator or modulator of innate immune cells, and it is also considered as a potential damage-associated molecular pattern (DAMP) [28]. Due to the fact that Gal-3 does not bear a typical ER-targeting sequence which would deliver it into a classical secretory pathway, it is secreted through a “leaderless” pathway. Although the precise mechanism by which it exits the cell is not yet fully understood, some details have been elucidated. For instance, a short amino acid sequence close to the N-terminal portion of the protein is known to be required for its extracellular translocation [29]. Gal-3 expression is increased in various epithelial and myeloid cells by microbial and nonmicrobial inflammatory stimuli. Among nonmicrobial stimuli, it is known that Gal3 is expressed on the surface of human monocytes and its expression level increases upon differentiation to macrophages. Mo (...truncated)