Pre-activation of TLR3 enhances the therapeutic effect of BMMSCs through regulation the intestinal HIF-2α signaling pathway and balance of NKB cells in experimental alcoholic liver injury

Increased intestinal permeability and immune disorder are important mechanisms of alcoholic liver disease (ALD). Recent evidences suggest bone marrow derived mesenchymal stem cells (BMMSCs) have protective effects on end-stage liver disease and intestinal barrier injury. Moreover, the activation of toll-like receptor 3 (TLR3) has been shown enhancing therapeutic effects of BMMSCs in inflammatory bowel disease (IBD). However, the mechanism remains unclear. In current study, chronic-binge alcohol abuse model was employed to investigate the therapeutic effects of BMMSCs and BMMSCs pre-activated with TLR3 (P-BMMSCs) on alcohol-induced liver and intestine damage. C57BL/6 mice were divided into four groups with normal control, alcohol-fed model, alcohol-fed model with BMMSCs treatment and alcohol-fed model with P-BMMSCs treatment. Alcohol-fed mice were fed Lieber-DeCali diet containing 5% alcohol for four weeks and given alcohol intragastrically on the 28th day, but control group were fed isocaloric diet. BMMSCs and P-BMMSCs were injected into the treatment group three times. Results showed alcohol diet causing significant damage to intestinal barrier and liver. These were reversed by the treatment of BMMSCs, especially P-BMMSCs. Moreover, alcohol increased the expression of intestinal HIF-2α, the proportion of NKB cells and the level of serum IL-18, while BMMSCs or P-BMMSCs reduced these factors. In conclusion, BMMSCs, especially TLR3 pre-activated BMMSCs could be used to protect alcohol-induced intestine and liver injury.