Galectins as self/non-self recognition receptors in innate and adaptive immunity: an unresolved paradox

Abstract

Galectins are characterized by their binding affinity for β-galactosides, a unique binding site sequence motif, and wide taxonomic distribution and structural conservation in vertebrates, invertebrates, protista, and fungi. Since their initial description, galectins were considered to bind endogenous (“self”) glycans and mediate developmental processes and cancer. In the past few years, however, numerous studies have described the diverse effects of galectins on cells involved in both innate and adaptive immune responses, and the mechanistic aspects of their regulatory roles in immune homeostasis. More recently, however, evidence has accumulated to suggest that galectins also bind exogenous (“non-self”) glycans on the surface of potentially pathogenic microbes, parasites, and fungi, suggesting that galectins can function as pattern recognition receptors (PRRs) in innate immunity. Thus, a perplexing paradox arises by the fact that galectins also recognize lactosamine-containing glycans on the host cell surface during developmental processes and regulation of immune responses. According to the currently accepted model for non-self recognition, PRRs recognize pathogens via highly conserved microbial surface molecules of wide distribution such as LPS or peptidoglycan (pathogen-associated molecular patterns; PAMPs), which are absent in the host. Hence, this would not apply to galectins, which apparently bind similar self/non-self molecular patterns on host and microbial cells. This paradox underscores first, an oversimplification in the use of the PRR/PAMP terminology. Second, and most importantly, it reveals significant gaps in our knowledge about the diversity of the host galectin repertoire, and the subcellular targeting, localization, and secretion. Furthermore, our knowledge about the structural and biophysical aspects of their interactions with the host and microbial carbohydrate moieties is fragmentary, and warrants further investigation.

The Ciona intestinalis immune-related galectin genes (CiLgals-a and CiLgals-b) are expressed by the gastric epithelium

“…Outstanding research by using real-timePCR analysis on the gut of naïve and LPS-inoculated ascidians, could contribute in disclosing the potential defence role of CiLgals in the gut. However, based on the known properties of the galectins, the CiLgals may also be involved in mucopolysaccharides processing, intracellular functions, and proliferation pathway of undifferentiated cells [2,6,7].…”

Evolution and Immune Function of Fish Lectins

“…73 Duplication and divergence events can explain the evolution of the various chordate galectins 56,62 while multiple lectin gene copies, allelic variation, or posttranslational modifications of the gene products expanded the molecular diversity and recognition capabilities. 57 …”

“…1 The homodimer is necessary for the binding and signaling on the cell surface. [57][58][59] The chimera-type galectins have a C-terminal similar to the prototype and a non-CRD N-terminal domain rich in proline and glycine. The N-terminal domain with collagen-like sequences in the presence of multivalent carbohydrate ligands could result in oligomerization.…”

“…59 Although the number of genes is different in various species, the galectin structures are well conserved among invertebrates and vertebrates. 57,62,63 They play important roles in morphogenesis, cell proliferation, cell death, tumor functions, and numerous pathological processes. 1,[62][63][64][65][66][67] A substantial number of galectins from the three different types have been identified and characterized in various tissues, plasma, and mucus of elasmobranch and teleost fish, which show structural and binding specificity conservation with mammalian counterparts.…”

“…54 The first galectin was identified and characterized from the electric organs of the electric eel Electrophorus electricus, 55 and since then members of the galectin family have been found in mammals, birds, amphibians, fish, nematodes, sponges, and some fungi. 1,56,57 Based on their domain organization, mammalian galectins have been classified in three types: "proto," "chimera," and "tandem-repeat." 1 Prototype galectins contain one CRD per subunit and are usually homodimers of noncovalently linked subunits.…”