Modulating intestinal function by fingolimod contributes to pancreatic immune tolerance in non-obese diabetic mice
Description
Gut barrier dysfunction aggravates the progression of type 1 diabetes (T1D). Fingolimod (FTY720) ameliorates numerous preclinical models of colitis, prevents the loss of tight junction proteins in diabetic retinopathy and a variety of barrier related diseases. However, its protective effects on T1D via gastrointestinal route and the underlying mechanisms remain unclear. FTY720 (1 mg/kg) was administered daily to inbred type 1 diabetes prone non-obese diabetic (NOD) mice by gavage. Gut microbiota composition, gut barrier function, gut-pancreas immune responses and T1D incidence were analyzed. The inhibiting effects of FTY720 on the migration of intestinal bacteria/intestinal immune cells to pancreas were further investigated by fluorescence labeling and flow cytometry. The results showed that FTY720 treatment significantly enhanced colonic barrier, suppressed intestinal bacteria translocation to pancreas. Furthermore, FTY720 reduced enteric pathogens Proteobacteria clusters and inhibited it-mediated TLR2/4-NF-κB-NLRP3 pathway, which contributed to suppressed activation of CD45+ leukocyte/CD4+ T cells and their migration to pancreas, reduced T helper type 1 cells (Th1 cells) differentiation, enhanced macrophage polarization to the anti-inflammatory M2 macrophages, thus attenuating T1D as evidenced by reduced T1D incidence and alleviatived insulitis. The inhibition of pancreatic autoimmunity by FTY720 may be also associated with increased regulate T cells (Tregs) in pancreas. Our data demonstrate that FTY720 inhibits pancreas-directed autoimmunity by restoring intestinal homeostasis (microbial homeostasis and immune homeostasis), providing novel insights into the anti-diabetes mechanisms of FTY720.
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Institutions
- Jiangnan University