Dichotomous effects of Galectin-9 in disease modulation in murine models of inflammatory bowel disease

: Inflammatory bowel disease (IBD) is a multifaceted disease characterised by compromised integrity of the epithelial barrier, the gut microbiome, and mucosal inflammation. While leukocyte recruitment and infiltration into intestinal tissue are well-studied and targeted in clinical practice, the role of galectins in modulating mucosal immunity remains underexplored. Galectins, a family of lectin-binding proteins, mediate critical interactions between immune cells and the intestinal epithelium. This study investigated the effect of endogenous Galectin-9 (Gal-9), as well as the combined effects with Galectin-3 (Gal-3), in modulating disease progression in murine models of colitis, using global knockout (KO) models for Gal-3, Gal-9, and Gal-3/Gal-9. Global deficiency in both galectins demonstrated improved disease parameters in Dextran sodium sulfate (DSS)-driven colitis. In contrast, in a model of adoptive T cell driven colitis, the addition of recombinant Gal-9 (rGal-9) was associated with reduced intestinal inflammation and an improvement in disease parameters. Further in vitro studies revealed no change in bone marrow-derived macrophage cytokine production in the absence of endogenous Gal-9, whereas the addition of rGal-9 to human macrophages stimulated pro-inflammatory cytokine production. Collectively, these findings demonstrate that Gal-9 plays distinct, context-dependent effects in intestinal inflammation, with both pro-inflammatory and anti-inflammatory effects. The contrasting functions of endogenous and exogenous Gal-9 underscore its complex involvement in IBD pathogenesis and highlight the need to differentiate its physiological function from therapeutic applications.