Abstract
Galectins, a family of animal lectins characterized by their affinity for N-acetyllactosamine-enriched glycoconjugates, modulate several immune cell processes shaping the course of innate and adaptive immune responses. Through interaction with a wide range of glycosylated receptors bearing complex branched N-glycans and core 2-O-glycans, these endogenous lectins trigger distinct signaling programs thereby controling immune cell activation, differentiation, recruitment and survival. Given the unique features of mucosal inflammation and the differential expression of galectins throughout the gastrointestinal tract, we discuss here key findings on the role of galectins in intestinal inflammation, particularly Crohn’s disease, ulcerative colitis, and celiac disease (CeD) patients, as well as in murine models resembling these inflammatory conditions. In addition, we present new data highlighting the regulated expression of galectin-1 (Gal-1), a proto-type member of the galectin family, during intestinal inflammation in untreated and treated CeD patients. Our results unveil a substantial upregulation of Gal-1 accompanying the anti-inflammatory and tolerogenic response associated with gluten-free diet in CeD patients, suggesting a major role of this lectin in favoring resolution of inflammation and restoration of mucosal homeostasis. Thus, a coordinated network of galectins and their glycosylated ligands, exerting either anti-inflammatory or proinflammatory responses, may influence the interplay between intestinal epithelial cells and the highly specialized gut immune system in physiologic and pathologic settings.
Highlights
DECIPHERING GLYCOCODES IN IMMUNITYComplex sugar structures play essential roles as hardware for storage of biological information, which can be deciphered by endogenous glycan-binding proteins or lectins [1]
We found that Th1- and Th17-differentiated cells express the repertoire of cell surface glycans that are critical for Gal-1 binding and induction of apoptosis; whereas Th2 cells are protected from this lectin through α2,6-sialylation of surface glycoproteins [43]
Since several immunoregulatory mechanisms are dysregulated in mucosal tissue of celiac disease (CeD) patients [108] and Gal-1 displays broad tolerogenic and anti-inflammatory activities in mucosal tissues [29], we evaluated the expression of this lectin in biopsies of CeD patients with or without gluten withdrawal (Table 1)
Summary
Complex sugar structures play essential roles as hardware for storage of biological information, which can be deciphered by endogenous glycan-binding proteins or lectins [1]. Galectins can tailor adaptive immunity by influencing T-cell signaling and activation, modulating T-cell survival, controlling the suppressive function of regulatory T cells (Tregs), altering the cytokine balance and regulating B-cell maturation and differentiation [3] Both the specificity of the CRD as well as glycan presentation in the corresponding receptors make distinct contributions to the specific effects of individual galectins, selectively mediating different biological processes. An increased number of Foxp3+ cells was observed in CeD-GFD patients (Figures 2J–L), which positively correlated with Gal-1 expression, suggesting activation of a circuit of immunosuppressive events leading to restoration of mucosal homeostasis. Modulation of Gal-1 expression during CeD development appeared to be specific as no differences were found in the expression of Gal-4, suggesting selective regulation of individual galectins during mucosal inflammation
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