The glycan-binding protein galectin-1 controls survival of epithelial cells along the crypt-villus axis of small intestine

MUGLIA CECILIA; MERCER NATALIA; TOSCANO MARTA; SCHATTNER MIRTA; POSNER ROBERTO; CERLIANI JUAN P; PAPPA GOBI RODRIGO; RABINOVICH GABRIEL; DOCENA GUILLERMO H.

Cell Death and Disease

ELSEVIER SCIENCE INC

Año: 2011 p. 163 - 174

2041-4889

The intestinal mucosa is continuously challenged by a variety of antigens from the diet and from commensal or pathogenic microorganisms, which should be carefully discriminated in order to either mount an active immune response or to promote immune tolerance (1). Epithelial cells, which are critical in this regulatory pathway, differentiate from stem cells located in the crypts and undergo a highly regulated maturation program as they migrate along the crypt–villus axis, forming a dynamic renewing tissue that maintains the integrity of the intestinal epithelium (2). As enterocytes migrate upwards along the axis, they acquire a mature absorptive phenotype, and are finally eliminated by apoptosis at the top of the villus. Several signaling cascades control cellular proliferation, differentiation, migration, and apoptosis of enterocytes (3,4). Furthermore, different metabolites (iron, vitamins, amino acids, carbohydrates and lipids) (6) and relevant enzymes including acyl-CoA synthetase serve as regulatory mediators that contribute to enterocyte renewal in the human intestine (6). However, the cellular and molecular mechanisms underlying the regulation of apoptosis of senescent enterocytes, which are of vital importance for the maintenance of mucosal homeostasis, are still poorly understood. Galectin-1 (Gal-1), an evolutionarily conserved â-galactoside binding protein, plays key roles in a variety of physiologic and pathologic processes (6,7). These functions include suppression of T cell responses through selective induction of TH1 and TH17 cell apoptosis (6-8) and activation of tolerogenic circuits on dendritic cells (9). These glycosylation-dependent functions account for the capacity of this lectin to dampen inflammation in autoimmune and chronic inflammatory disorders (6,10-13), and to favor immune escape of certain types of cancer (13-16). Gal-1 is expressed in different portions of the human and mouse gastrointestinal tract (17,18), and similar to other members of the galectin family, it has been implicated in different intestinal disorders (19-21). Gal-1 expression is down-regulated in a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colits and its therapeutic administration contributes to the reduction of TH1 and pro-inflammatory cytokines (TNF, IL-1â, IL-12 and IFN-ã), and to remission of the clinical signs of inflammatory bowel disease (11). On the other hand, overexpression of Gal-1 has been linked to the progression of human colon carcinomas (22). Galectins have been implicated in the homeostasis of different mucosa. In this regard, interaction of Gal-3 and epithelial cell mucins has been shown to be critical to maintain the ocular surface epithelial barrier (23). To gain a more complete understanding of the role of protein-glycan interactions in mucosal tissue, the present study was conducted to elucidate the role of Gal-1 within the intestinal epithelial cell compartment. We found that Gal-1 binds to human and mouse enterocytes where it signals apoptosis through a caspase-dependent mechanism, leading to depolarization of the mitochondrial membrane and caspase-3 activation. Accordingly, mice lacking Gal-1 (Lgals1-/-) have longer duodenal villi and exhibit a more pronounced deleterious response upon starvation compared to wild-type mice, suggesting that Gal-1 may be involved in overall regulation of enterocyte turnover in the villus, thus contributing to small bowel homeostasis.