Haematopoietic prolyl hydroxylase‐1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis

Abstract

Prolyl hydroxylase domain-containing proteins (PHDs) regulate the adaptation of cells to hypoxia. Pan-hydroxylase inhibition is protective in experimental colitis, in which PHD1 plays a prominent role. However, it is currently unknown how PHD1 targeting regulates this protection and which cell type(s) are involved. Here, we demonstrated that Phd1 deletion in endothelial and haematopoietic cells (Phd1 Tie2:cre) protected mice from dextran sulphate sodium (DSS)-induced colitis, with reduced epithelial erosions, immune cell infiltration, and colonic microvascular dysfunction, whereas the response of Phd2 Tie2:cre and Phd3 Tie2:cre mice to DSS was similar to that of their littermate controls. Using bone marrow chimeras and cell-specific cre mice, we demonstrated that ablation of Phd1 in haematopoietic cells but not in endothelial cells was both necessary and sufficient to inhibit experimental colitis. This effect relied, at least in part, on skewing of Phd1-deficient bone marrow-derived macrophages towards an anti-inflammatory M2 phenotype. These cells showed an attenuated nuclear factor-κB-dependent response to lipopolysaccharide (LPS), which in turn diminished endothelial chemokine expression. In addition, Phd1 deficiency in dendritic cells significantly reduced interleukin-1β production in response to LPS. Taken together, our results further support the development of selective PHD1 inhibitors for ulcerative colitis, and identify haematopoietic cells as their primary target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Prediction of steroid demand in the treatment of patients with ulcerative colitis by immunohistochemical analysis of the mucosal microenvironment and immune checkpoint: role of macrophages and regulatory markers in disease severity

“…The candidate genes provide potentially important insights into the disease pathogenesis as many of them are related to the immune system pathways such as cytokine receptor interaction, IgG binding, cytokine activity, macrophage activation and positive regulation of activated T cell proliferation. Candidate genes are TNFRSF14 (HVEM), TNFRSF9, IL1R2, IL8RA‐IL8RB, IL7R, IL10, IL12B, DAP, PRDM1 (BLIMP1), JAK2, IRF5, GNA12 and LSP , among others. Therefore, our markers agree with the current understanding of UC susceptibility and pathogenesis.…”

The PHD1 oxygen sensor in health and disease

“…; Van Welden et al . ). Furthermore, IL‐1β‐induced NF‐κB activity is also significantly decreased upon combined deletion of PHD1 and FIH (Scholz et al .…”

“…A more recent study supports a role for PHD1 in colitis by showing that loss of PHD1 in the haematopoietic system is sufficient to protect against colitis (Van Welden et al . ). This effect is in part mediated by an anti‐inflammatory M2‐polarization of PHD1 −/− macrophages.…”

“…) and the promotion of an anti‐inflammatory M2 phenotype in macrophages (Van Welden et al . ). However, to advance the use of hydroxylase inhibitors for human IBD, potential unwanted adverse side effects of PHIs need to be considered.…”

Hypoxia‐sensitive pathways in intestinal inflammation

“…Similarly to the previously mentioned study, deletion of PHD3 or heterozygous deletion of PHD2 in haematopoietic cells was not protective (Van Welden et al . ). Further support for the involvement of PHD1 in IBD is the finding that in human colonic biopsies PHD1 protein levels are elevated in both UC and CD patients (Van Welden et al .…”