Epigenetically modulating macrophage subpopulations to promote long-term allograft survival in a mouse heart transplant model

Despite much-improved protocols that broadly suppress the adaptive immune cells, most allografts are still lost to chronic rejection, in which macrophages have been prominently featured in the graft. In both clinical and preclinical studies, the graft-infiltrating macrophages often acquire diverse effector activities, especially the M2-biased programs, to mediate graft damage. But the precise mechanisms that regulate such programs remain incompletely defined. In the present study, we took a genome-wide approach to profile the epigenomic changes of M2 polarized macrophages and uncovered bromodomain and extraterminal domain family protein-4 (BRD4) as a critical epigenetic regulator of M2 cells. Further in vitro studies revealed that either blocking BRD4 using a chemical inhibitor or conditional deletion of Brd4 in myeloid cells profoundly inhibited the induction of M2 cells. Moreover, in a fully major histocompatibility complex–mismatched heart transplant model, in which treatment with cytotoxic T lymphocyte antigen-4 Ig fusion protein led to the development of chronic rejection, inhibition of BDR4 in transplant recipients resulted in long-term heart allograft survival, which was associated with diminished intragraft M2 cells and absence of histologic features of chronic rejection. Together, our data suggest that macrophages can be epigenetically modified in favor of transplant survival and that BRD4 seems a promising therapeutic target for blocking chronic allograft rejection.