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

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

J Pathol. 2016 Dec 16;:

Authors: Van Welden S, De Vos M, Wielockx B, Tavernier SJ, Dullaers M, Neyt S, Descamps B, Devisscher L, Devriese S, Van den Bossche L, Holvoet T, Baeyens A, Correale C, D'Alessio S, Vanhove C, De Vos F, Verhasselt B, Breier G, Lambrecht BN, Janssens S, Carmeliet P, Danese S, Elewaut D, Laukens D, Hindryckx P

Abstract
Prolyl hydroxylase domain-containing proteins (PHD) 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(f/)(f) 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(f/+) Tie2:cre and Phd3(f/)(f) Tie2:cre mice to DSS was similar to their littermate controls. Using bone marrow chimeras and cell-specific cre mice we could demonstrate that ablation of Phd1 in haematopoietic cells but not 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 NF-κB-dependent response to lipopolysaccharide (LPS) which in turn diminished endothelial chemokine expression. In addition, Phd1-deficiency in dendritic cells significantly reduced interleukin (IL)-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.

PMID: 27981571 [PubMed - as supplied by publisher]

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