L-arginine and L-arginine-metabolizing enzymes play important roles in the immune system. Arg1 is one of the key enzymes in L-arginine metabolism and plays critical roles in the biological function of myeloid cells, including macrophage polarization and suppressive function of myeloid-derived suppressor cells. In this study we provide evidence for a novel role of Arg1 in the regulation of myeloid dendritic cells (DCs) differentiation. Expression of Arg1 and thus the L-arginine usage was dramatically induced during the course of mouse DC differentiation. Modulation of Arg1 expression in mouse bone marrow affects DC differentiation. Mechanistic studies showed that the induction of Arg1 in differentiating DCs was caused by an increased recruitment of HDAC4 to Arg1 promoter, which led to decreased acetylation of both Histone 3 and STAT6 proteins and subsequent transcriptional activation of Arg1. Further ChIP analysis identified a novel STAT6 binding site on Arg1 promoter that was essential for HDAC4-mediated Arg1 regulation. In addition, over-expression of Arg1 abrogated the suppressive effect of HDAC inhibitor on DC differentiation. In summary, this study reveals that Arg1 is a novel regulator of DC differentiation and that cross-talk between HDAC4 and STAT6 is the pathway that regulates Arg1 transcription during DC differentiation.
- Copyright © 2013 by The American Association of Immunologists, Inc.