CONICET | Buscador de Institutos y Recursos Humanos

Background: Interactions between glycans and endogenous lectins are crucial in the development and resolution of many chronic inflammatory diseases. Galectin-1 (Gal-1) is a glycan-binding protein that recognizes N- and O-glycans bearing terminal lactosamine (Gal[beta](1-4)GlcNAc) units. However, modification of this structure with [alpha](2,6) sialic acid is restrictive for Gal-1 binding. Gal-1 is capable of exerting immunomodulatory activity in different chronic inflammation models in mice, such as collagen-induced arthritis and experimental autoimmune encephalomyelitis. Administration of recombinant Gal-1 protects against the development of 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis, both in an acute and chronic TNBS-models. Nevertheless, the role of endogenous Gal-1 in mucosal homeostasis and intestinal immune regulation is still poorly understood. An improved understanding of the mechanisms underlying the anti-inflammatory activity of Gal-1 in intestinal inflammation may reveal a potential alternative treatment for human IBD.Methods: We optimized a model of TNBS-induced colitis and evaluated the outcome of the disease and its resolution in C57BL/6 wild-type (WT) and Gal-1 knock-out (Lgals1-/-, Gal-1 KO) mice. We also studied the development of experimental colitis in C57BL/6 mice deficient in glycosyltransferases involved in the generation or masking of Gal-1-specific glycoepitopes: C2GnT-1 (C2gnt1-/-, C2GnT-1 KO) involved in the generation of core-2 O-glycans (Gal-1 permissive glycoepitopes), and St6gal1 (St6gal1-/-, St6gal1 KO) responsible for terminal [alpha](2,6) sialylation of N-glycans (masking Gal-1-specific glycoepitopes).Results: TNBS-treated mice developed acute colitis both in WT (P < 0.05) and Lgals1-/- (P < 0.01) mice, although a more severe disease in animals lacking endogenous Gal-1 was observed (P < 0.05). TNBS-treated Lgals1-/- mice could not recover from wasting disease, while their WT counterpart progressively gained weight over time. Evaluation of macroscopic intestinal inflammation by colon weight/length ratio showed that TNBS-treated Lgals1-/- mice exhibited a higher degree of inflammation when compared to either controls (P < 0.01) or WT treated mice (P < 0.05). TNBS-treated WT mice showed a higher proportion of CD4+CD25+Foxp3+ Treg cells in mesenteric lymph nodes (MLN) when compared to controls (P < 0.05), that was not seen in Gal-1 KO mice. In colonic lamima propria (cLP) a higher proportion of CD8+ T lymphocytes was observed and a decreased Treg/CD8+ ratio in TNBS-treated Lgals1-/- mice, when compared with their WT counterpart. Quantification of T helper cytokines by RT-qPCR in colon showed that TNBS-treated Gal-1 KO mice presented high levels of IFN-[gamma] mRNA whereas TNBS-treated WT mice presented high levels of IL-17 but not IFN-[gamma] mRNA, suggesting a differential T response between these 2 genotypes. C2gnt1-/- mice developed a more severe TNBS-induced colitis with high mortality rate, whereas St6gal1-/- mice developed an attenuated form of colitis (P < 0.001). The differential impact of the experimental colitis in these 2 genotypes was correlated with a higher proportion of CD4+Gal-1+ lymphocytes both in MLN and cLP (P < 0.05), and a higher frequency of CD8+Gal-1+ lymphocytes only in MLN (P < 0.01) in St6gal1 KO mice, when compared to C2GnT-1 KO mice.Conclusions: These results highlight the critical role of endogenous Gal-1 and its specific glycans in regulating mucosal homeostasis and T cell function during the development of inflammatory bowel diseases, suggesting potential avenues for modulating intestinal inflammation through the control of lectin-carbohydrate interactions.