Trans-activation of eotaxin-1 by Brg1 contributes to liver regeneration

Abstract

Infiltration of eosinophils is associated with and contributes to liver regeneration. Chemotaxis of eosinophils is orchestrated by the eotaxin family of chemoattractants. We report here that expression of eotaxin-1 (referred to as eotaxin hereafter), but not that of either eotaxin-2 or eotaxin-3, were elevated, as measured by quantitative PCR and ELISA, in the proliferating murine livers compared to the quiescent livers. Similarly, exposure of primary murine hepatocytes to hepatocyte growth factor (HGF) stimulated eotaxin expression. Liver specific deletion of Brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuated eosinophil infiltration and down-regulated eotaxin expression in mice. Brg1 deficiency also blocked HGF-induced eotaxin expression in cultured hepatocytes. Further analysis revealed that Brg1 could directly bind to the proximal eotaxin promoter to activate its transcription. Mechanistically, Brg1 interacted with nuclear factor kappa B (NF-κB)/RelA to activate eotaxin transcription. NF-κB knockdown or pharmaceutical inhibition disrupted Brg1 recruitment to the eotaxin promoter and blocked eotaxin induction in hepatocytes. Adenoviral mediated over-expression of eotaxin overcame Brg1 deficiency caused delay in liver regeneration in mice. On the contrary, eotaxin depletion with RNAi or neutralizing antibodies retarded liver regeneration in mice. More important, Brg1 expression was detected to be correlated with eotaxin expression and eosinophil infiltration in human liver specimens. In conclusion, our data unveil a novel role of Brg1 as a regulator of eosinophil trafficking by activating eotaxin transcription.