Hypoxia‐inducible factor controls immunoregulatory properties of myeloid cells in mouse cardiac allografts – an experimental study

Summary Hypoxia‐inducible factors ( HIF s) play a critical role in inflammatory properties of myeloid‐derived cells. The effect of HIF s on myeloid‐derived cell functions in organ transplantation remains unknown, however. We transplanted hearts into transgenic mice with myeloid cell‐targeted deletions of HIF ‐1α or its negative regulator von Hippel–Lindau ( VHL ) to investigate the effects of HIF ‐1α inactivation or HIF pathway activation, respectively, on ischemia‐reperfusion injury ( IRI ) and acute rejection. Deletion of VHL in myeloid cells enhanced mRNA expression of anti‐inflammatory genes IDO , Arg‐1, and HO ‐1 in vitro . In vivo , VHL −/− myeloid‐derived cells of allograft recipients alleviated IRI and acute rejection, evidenced by reduced cardiomyocyte damage, decreased proinflammatory cytokine mRNA levels, and absence of inflammatory infiltrate at 5 days after transplantation. Ultimately, allograft survival was significantly prolonged. In vitro , VHL −/− myeloid‐derived cells dose‐dependently inhibited T‐cell proliferation. Myeloid cells with HIF ‐1α‐deletion retained proinflammatory qualities in vitro and in vivo . Deletion of VHL in myeloid cells of nonimmunosuppressed cardiac allograft recipients reduced myocardial injury and acute rejection. We suggest that HIF transcription factors induce a regulatory phenotype in myeloid‐derived cells, which may be harnessed as a novel therapeutic strategy to regulate immune responses after heart transplantation.