Galectin-1 (Gal1) as a key modulator of intestinal inflammation in the TNBS-induced colitis model: a potential therapeutic application of Gal1

MARIÑO KV.; MAY M; MENDEZ-HUERGO S; MOROSI L; TOSCANO MA; MORALES R; CUTINE AM; RABINOVICH GA; GATTO S; CAGNONI AJ

San Francisco

Simposio; Kenneth Rainin Foundation Innovation Symposium; 2017

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 models of inflammatory diseases including an 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: Could exogenous Gal1 or its tailored designed recombinant Gal1 variants (resistant to acidosis and oxidation), act as immunosuppressive agents to dampen intestinal inflammation?Methods: We evaluated the development of TNBS-induced colitis both in wild-type (WT) animals and in mice devoid of Gal1 (Gal1KO). We also assessed the therapeutic effects of Gal1 and its improved variants, both in vitro and in vivo. In vitro experiments included T-cell proliferation and cytokine production; in vivo, we evaluated disease progression by body weight, changes in immune responses and histopathological scores.Results: Gal1-deficient mice could not recover from experimental colitis, as their WT counterpart. Moreover, prophylactic Gal1 administration partially rescued KO animals, alleviating the disease symptoms. WT mice presented a TH17-biased response in colon, while Gal1KO mice failed to switch from a TH1 to a TH17 response. Tailored-designed Gal1 variants showed uncoupled immunomodulatory activity. Decoupling of biological functions in Gal1 variants resulted in a more efficient therapeutic Gal1 effect in the TNBS experimental model of colitis.Conclusions: An alteration in Gal-1-glycan interactions impairs resolution of intestinal inflammation. Rational design resulted in Gal1 variants that could be used to selectively dampen intestinal inflammation.Impact on our knowledge of IBD: Galectin-1 has a key role in maintaining mucosal homeostasis, as demonstrated in the TNBS-model. Decoupling of biological functions in Gal1 variants could result in specific therapeutic application of these variants at different stages of disease.