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.
| Original language | English |
|---|---|
| Pages (from-to) | 547-558 |
| Number of pages | 12 |
| Journal | Journal of Pathology |
| Volume | 241 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Mar 1 2017 |
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Keywords
- dendritic cells
- haematopoietic cells
- macrophages
- prolyl hydroxylase-1
- ulcerative colitis
ASJC Scopus subject areas
- Pathology and Forensic Medicine
Cite this
Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis. / Van Welden, Sophie; De Vos, Martine; Wielockx, Ben; Tavernier, Simon J.; Dullaers, Melissa; Neyt, Sara; Descamps, Benedicte; Devisscher, Lindsey; Devriese, Sarah; Van den Bossche, Lien; Holvoet, Tom; Baeyens, Ann; Correale, Carmen; D'Alessio, Silvia; Vanhove, Christian; De Vos, Filip; Verhasselt, Bruno; Breier, Georg; Lambrecht, Bart N.; Janssens, Sophie; Carmeliet, Peter; Danese, Silvio; Elewaut, Dirk; Laukens, Debby; Hindryckx, Pieter.
In: Journal of Pathology, Vol. 241, No. 4, 01.03.2017, p. 547-558.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis
AU - Van Welden, Sophie
AU - De Vos, Martine
AU - Wielockx, Ben
AU - Tavernier, Simon J.
AU - Dullaers, Melissa
AU - Neyt, Sara
AU - Descamps, Benedicte
AU - Devisscher, Lindsey
AU - Devriese, Sarah
AU - Van den Bossche, Lien
AU - Holvoet, Tom
AU - Baeyens, Ann
AU - Correale, Carmen
AU - D'Alessio, Silvia
AU - Vanhove, Christian
AU - De Vos, Filip
AU - Verhasselt, Bruno
AU - Breier, Georg
AU - Lambrecht, Bart N.
AU - Janssens, Sophie
AU - Carmeliet, Peter
AU - Danese, Silvio
AU - Elewaut, Dirk
AU - Laukens, Debby
AU - Hindryckx, Pieter
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - dendritic cells
KW - haematopoietic cells
KW - macrophages
KW - prolyl hydroxylase-1
KW - ulcerative colitis
UR - http://www.scopus.com/inward/record.url?scp=85011340504&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011340504&partnerID=8YFLogxK
U2 - 10.1002/path.4861
DO - 10.1002/path.4861
M3 - Article
AN - SCOPUS:85011340504
VL - 241
SP - 547
EP - 558
JO - Journal of Pathology
JF - Journal of Pathology
SN - 0022-3417
IS - 4
ER -