Fingolimod-mediated intestinal homeostasis induces pancreatic immune tolerance in autoimmune diabetes
Intestinal disorder aggravates the progression of type 1 diabetes (T1D). Fingolimod (FTY720), an agonist of sphingosine-1-phosphate-1-receptors, has shown potential in the treatment of several autoimmune diseases, including T1D. Herein, we investigated the role and possible mechanism of FTY720 on intestinal dysfunction, further contributes to pancreatic immune tolerance in non-obese diabetic (NOD) mice. In present study, our data demonstrated FTY720 markedly attenuated intestinal microbial dysbiosis, evidencing by reduced intestinal pathogenic Proteobacteria clusters and enhanced butyrate-producing bacteria. In addition, FTY720 treatment significantly suppressed intestinal bacteria translocation and enhanced the expression of tight junction proteins including ZO-1, ZO-2 and Occludin. We further identified that FTY720 inhibited the expression of toll like receptor 2/4 and the activation of nuclear factor-κB as well as its downstream NOD like receptor protein 3 inflammasome in colon of NOD mice. Finally, FTY720 markedly suppressed intestinal CD45+/CD4+ T cells activation, T helper type 1 cells differentiation and enhanced macrophage polarization to the anti-inflammatory M2 macrophages, which contributed to the maintenance of pancreatic immune balance and reduced T1D incidence in NOD mice. Our data clearly demonstrated that maintaining intestinal homeostasis by FTY720 contributed to its anti-diabetes in NOD mice.