You Can't Run From Inflammation

Abstract

### Macrophage Skewing by Phd2 Haplodeficiency Prevents Ischaemia by Inducing Arteriogenesis Takeda et al Nature . 2011;479:122–126. Prolyl hydroxylase domain (PHD) molecules sense oxygen availability in mammalian cells and can serve as drug targets. Recent work from Takeda et al suggest a previously unappreciated role for PHD2—the main HIF prolyl hydroxylase—in arteriogenesis via macrophage skewing. Deletion of PHD2 in macrophages associated with activation of the canonical NF-κB pathway and arteriogenesis. Work done by many investigators over the last decade has shed light onto the mechanisms of oxygen sensing in cells and in organisms.1 The prolyl hydroxylase domain (PHD; also called EglN) proteins belong to a family of Fe(II) and 2-oxoglutarate–dependent dioxygenases, whose activity depends on oxygen bioavailability.2 One well-described substrate of PHDs is the master transcription factor hypoxia-inducible factor (HIF). HIF hydroxylation by PHDs targets HIF for degradation; hence, PHDs inhibit HIF activity. Whereas mammalian cells contain 3 PHD isoforms, PHD2 appears to be the primary HIF prolyl hydroxylase, although other PHD family members (PHD1 and PHD3) can contribute to HIF regulation in certain conditions.2 Multiple lines of evidence suggest that PHD molecules (particularly PHD2) act as “oxygen sensors” in mammalian cells. For example, genetic knockdown of PHD2 in mice recapitulates many of the hallmarks of hypoxia in vivo.3 In a recent paper in Nature , Mazzone and colleagues4 describe a novel, and previously unappreciated, …