Sphingosine-1-phosphate lyase inhibition exacerbates DSS-induced colitis via promoting the disruption of epithelial barrier

Abstract

Abstract S1P is a bioactive sphingolipid that participates as a critical regulator of many physiological processes, mainly in lymphocyte egress from lymphoid tissue, mediated by S1P gradients through the activity of S1P lyase (SPL). Inhibition of both S1P-specific receptors and Lyase activity has been shown to improve inflammatory conditions during Crohn’s-like ileitis. In contrast to this, initial observations show acute DSS-induced colitis was aggravated by SPL inhibition. Here we investigate whether the inhibition of Lyase in the intestinal epithelium is the cause of the exacerbation of colitis. To induce global or epithelial cell specific SPL deletion, Gt(rosa)-cre or Villin-cre Sgpl1 transgenic mice were administered with tamoxifen (80 mg/kg) by oral gavage for 5 consecutive days. Then, mice were treated with DSS (2.5%) in drinking water for 7 days. Clinical features and histological scores were recorded. Permeability assays were performed to evaluate integrity of the intestinal epithelium with fluorescein isothiocyanate (FITC)-dextran 4 kDa. Significant differences in the histopathological features (inflammation and injury) in colon were observed between Gt(rosa)Cre+/−/SPL−/− or VillinCre+/−/SPL−/− mice compared to their respective controls (without tamoxifen treatment) (n>10, p<0.001). In addition, these animals presented higher levels of epithelial permeability since the concentration of serum (FITC)-dextran was higher than their respective controls (n>10, p<0.001). In conclusion, in the acute model of DSS-induced colitis the presence of S1P in the intestinal epithelium exacerbates inflammatory conditions, demonstrating that there could be differences in the mechanisms with chronic models of IBD.