Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis

Abstract

PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage1–5. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion6–8. We show that Phd2 (also known as Egln1) haplodeficient (Phd2+/−) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2+/− mice was due to an expansion of tissue-resident, M2-like macrophages9,10 and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a proarteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2+/− macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.

Hypoxia-dependent regulation of inflammatory pathways in immune cells

“…While our understanding of the role of HIF hydroxylases in the regulation of immune cell function is far from complete, recent studies investigating individual HIF hydroxylase isoforms in discreet immune and epithelial cell subtypes have identified isoform-specific roles (80)(81)(82)(83)(84)(85)(86)(87)(88)(89). Notably, these phenotypes are not fully accounted for by downstream HIF-dependent effects, further supporting the existence of alternative hydroxylase-regulated pathways such as NF-κB in immune cells.…”

MiR-127 Modulates Macrophage Polarization and Promotes Lung Inflammation and Injury by Activating the JNK Pathway

“…4A, 4B). However, it has still remained controversial regarding the role of NF-kB in macrophage differentiation, as someone supported the M1-prone effect of NF-kB, whereas others argued that NF-kB was equally important in priming M1 or M2 gene transcription or even had a negative effect on M1 macrophage development (32)(33)(34). We thus turned to other major signaling pathways such as MAPKs, which prove to play an essential role in mediating inflammatory response upon TLR engagement.…”

Hydroxylases as therapeutic targets in inflammatory bowel disease

“…Subsequent studies revealed that the mechanism by which hypoxia leads to activation of NF-kB is also largely dependent upon altered HIF-hydroxylase activity. [57][58][59] Hydroxylase Inhibitors in Models of IBD As outlined above, hydroxylases are key oxygen sensors, which confer hypoxic sensitivity to transcriptional regulators including HIF and NF-kB, both of which are protective against colitis when activated in intestinal epithelial cells. As HIF and NF-kB are key regulators of both immune and inflammatory processes 35,37 it was initially proposed that pharmacologic hydroxylase inhibition, leading to enhanced HIF and NF-kB activity may be of therapeutic benefit in chronic inflammatory conditions such as IBD.…”