title: 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 (Phd1f/fTie2: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 Phd2f/+Tie2:cre and Phd3f/fTie2: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.
authors.affiliation: Department of Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Welden
authors.affiliation: Department of Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: De Vos
authors.affiliation: Heisenberg Research Group, Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Wielockx
authors.affiliation: Department of Internal Medicine, Ghent University, Ghent, Belgium.|Inflammation Research Centre VIB, Zwijnaarde, Belgium.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Tavernier
authors.affiliation: Inflammation Research Centre VIB, Zwijnaarde, Belgium.|Department of Pulmonary Medicine, Ghent University, Ghent, Belgium.
authors.forename: Melissa
authors.initials: M
authors.lastname: Dullaers
authors.affiliation: Laboratory of Radiopharmacy, Ghent University, Ghent, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Neyt
authors.affiliation: Infinity Imaging Laboratory (iMinds Medical IT-IBiTech-MEDISIP), Ghent University, Ghent, Belgium.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Descamps
authors.affiliation: Department of Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Devisscher
authors.affiliation: Department of Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Devriese
authors.affiliation: Department of Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Van den Bossche
authors.affiliation: Department of Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Holvoet
authors.affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Baeyens
authors.affiliation: IBD Centre, Department of Gastroenterology, Humanitas Clinical and Research Centre, Rozzano, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Correale
authors.affiliation: IBD Centre, Department of Gastroenterology, Humanitas Clinical and Research Centre, Rozzano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Alessio
authors.affiliation: Infinity Imaging Laboratory (iMinds Medical IT-IBiTech-MEDISIP), Ghent University, Ghent, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Vanhove
authors.affiliation: Laboratory of Radiopharmacy, Ghent University, Ghent, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: De Vos
authors.affiliation: Department of Clinical Chemistry, Microbiology, and Immunology, Ghent University, Ghent, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: Verhasselt
authors.affiliation: Division of Medical Biology, Department of Psychiatry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Breier
authors.affiliation: Department of Internal Medicine, Ghent University, Ghent, Belgium.|Inflammation Research Centre VIB, Zwijnaarde, Belgium.
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.affiliation: Department of Internal Medicine, Ghent University, Ghent, Belgium.|Inflammation Research Centre VIB, Zwijnaarde, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Janssens
authors.affiliation: Laboratory of Angiogenesis and Vascular metabolism, Vesalius Research Centre, KU Leuven, VIB, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: IBD Centre, Department of Gastroenterology, Humanitas Clinical and Research Centre, Rozzano, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.affiliation: Inflammation Research Centre VIB, Zwijnaarde, Belgium.|Department of Rheumatology, Ghent University, Ghent, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.affiliation: Department of Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Debby
authors.initials: D
authors.lastname: Laukens
authors.affiliation: Department of Gastroenterology, Ghent University, Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Hindryckx
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003713:Dendritic Cells / Q000187:drug effects / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; C522721:PHD1 protein, mouse; D011393:Procollagen-Proline Dioxygenase; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: dendritic cells; haematopoietic cells; macrophages; prolyl hydroxylase-1; ulcerative colitis