Galectin-1 and tailored designed Gal1 variants show different functionalities in experimental models of colitis

CUTINE, ANABELA; MOROSI, LUCIANO; CAGNONI, ALEJANDRO J; MENDEZ-HUERGO, SANTIAGO P.; MORALES, ROSA; GATTO, SABRINA; MAY, MARÍA; TOSCANO, MARTA A; RABINOVICH, GABRIEL A.; MARIÑO, KARINA VALERIA

San Francisco, USA

Conferencia; Kenneth Rainin Foundation Innovations Symposium; 2018

Kenneth Rainin Foundation

Background: Interactions between glycans and endogenous lectins are crucial in the development and resolution of many chronic inflammatory diseases. Galectin-1 (Gal1), a carbohydrate-binding protein, can exert protective immunomodulatory activity in the acute TNBS-model of colitis. However, the role of Gal1 and its carbohydrate ligands on the development and resolution of intestinal inflammation is still not well understood. The therapeutic potential of this anti-inflammatory lectin is hampered by its sensitivity to the inflammatory environment, as acidic and oxidative conditions negatively affect its activity.Hypothesis: Can exogenous Gal1 or its tailored designed recombinant Gal1 variants (resistant to acidosis and oxidation), dampen intestinal inflammation in experimental models of colitis with distinct disease mechanisms? Methods: We evaluated the role of endogenous Gal1 by comparing wild-type (WT) and Gal1-deficient mice (Gal1KO) in two models of intestinal inflammation, TNBS- and DSS-induced colitis. We also assessed the therapeutic effects of Gal1 and its improved variants in both models. Disease progression and severity were monitored by body weight, histopathological score and immunological features such as immune subpopulations and cytokines.Results: We found significant differences when comparing the role of Ga1 in TNBS- and DSS-induced colitis. Gal1KO mice displayed a more aggressive colitis than their WT counterparts in TNBS-induced colitis. However, in the chronic DSS model, mice showed no significant differences with WT animals regarding clinical and histological score and cytokine profile. Additionally, therapeutic administration of Gal1 to WT mice following TNBS treatment ameliorated clinical and histological score, yet it had no effect on DSS-induced colitis. Finally, administration of SG1 or SG2, tailored-designed variants of Gal1, resulted in a more efficient therapeutic effect in TNBS colitis while showing no improvement in DSS-induced inflammation.Conclusions: Results in TNBS-induced colitis validate both the key role of endogenous Gal1 in maintaining mucosal homeostasis, and the effectiveness of therapeutically administered recombinant Gal1 and its tailored variants to ameliorate colitis in a Th1/Th17-driven model. However, neither the lack of Gal1 nor its therapeutic administration could alter disease severity in the chronic Th2-skewed DSS model caused by death of epithelial cells, compromised barrier function.Impact on our knowledge of IBD: The therapeutic potential of Gal1 and its designed variants was confirmed in the TNBS-model, however, DSS-induced colitis did not respond to Gal1 administration; specific mechanisms involved in the initiation and perpetuation of disease pathogenesis may dictate Gal1 therapy. These results indicate that Gal1 could be a more suitable therapeutic option for Crohn´s disease rather than ulcerative colitis.