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

Sophie Van Welden, Martine De Vos, Ben Wielockx, Simon J. Tavernier, Melissa Dullaers, Sara Neyt, Benedicte Descamps, Lindsey Devisscher, Sarah Devriese, Lien Van den Bossche, Tom Holvoet, Ann Baeyens, Carmen Correale, Silvia D'Alessio, Christian Vanhove, Filip De Vos, Bruno Verhasselt, Georg Breier, Bart N. Lambrecht, Sophie JanssensPeter Carmeliet, Silvio Danese, Dirk Elewaut, Debby Laukens, Pieter Hindryckx

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)547-558
Number of pages12
JournalJournal of Pathology
Volume241
Issue number4
DOIs
Publication statusPublished - Mar 1 2017

Keywords

  • dendritic cells
  • haematopoietic cells
  • macrophages
  • prolyl hydroxylase-1
  • ulcerative colitis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Van Welden, S., De Vos, M., Wielockx, B., Tavernier, S. J., 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, B. N., ... Hindryckx, P. (2017). Haematopoietic prolyl hydroxylase-1 deficiency promotes M2 macrophage polarization and is both necessary and sufficient to protect against experimental colitis. Journal of Pathology, 241(4), 547-558. https://doi.org/10.1002/path.4861