MSCs-derived CRABP2 regulates Treg/CXCL1 to ameliorate alcohol-induced liver injury.

BACKGROUND

Alcoholic hepatitis (AH) is an inflammatory disease associated with high mortality. Mesenchymal stromal cells (MSCs) are promising immune regulators in modulating acute or chronic inflammation. However, the specific mechanism mediating the persistent inflammatory response during AH and therapeutic potential of MSCs remains unclear.

METHODS

We performed MSCs infusion on an animal model of acute-on-chronic alcohol-induced liver injury. Inducible depletion of regulatory T cells (Treg) was achieved using Foxp3-DTR/EGFP transgenic mice. MSCs and anti-CXCL1 treatments were performed on Treg-depleted mice to further elucidate the mechanisms of Treg-mediated neutrophil infiltration.

RESULTS

MSCs therapy ameliorated liver damage, and elevated the proportion of Treg by secreting cellular retinoic acid binding protein 2 (CRABP2). Treg deficiency exacerbated hepatic neutrophil infiltration upon alcohol stimulation, with elevated serum TNFα and the subsequent hepatocellular CXCL1 expression. Hepatic neutrophil infiltration in Treg-depleted mice cannot be reduced by MSCs or anti-CXCL1 treatment. Consistently, AH patients had decreased peripheral Treg proportion, with the activation of hepatic and peripheral CXCL1-neutrophil inflammatory axis.

CONCLUSIONS

Treg are critical protective regulators during acute alcohol-induced liver injury. MSCs-derived CRABP2 increases Treg proportion to ameliorate alcohol-induced liver injury through regulating CXCL1/neutrophil axis, appearing as a promising strategy for limiting the persistent inflammatory response during severe AH.