HIF-1α activation in myeloid cells accelerates dextran sodium sulfate-induced colitis progression in mice

Dis Model Mech. 2018 Jul 30;11(7):dmm033241. doi: 10.1242/dmm.033241.


Inflammatory bowel disease (IBD) is a chronic inflammatory disease, in which the intestinal epithelium loses its barrier function. Given the existence of the oxygen gradient in the intestinal epithelium and that inflammation further contributes to the tissue hypoxia, we investigated the role of hypoxia-inducible factor (HIF), a transcription factor activated under hypoxic conditions in myeloid cells, in the progression of IBD. To do this, we utilized myeloid-specific knockout (KO) mice targeting HIF pathways, created by a Cre-loxP system with human MRP8 (hMRP8), an intracellular calcium-binding protein, as the myeloid promoter. By feeding 5% dextran sodium sulfate (DSS) to hMRP8 von Hippel Lindau (Vhl) KO mice, in which HIF-1α and HIF-2α are constitutively activated in myeloid cells, we found that these mice were highly susceptible to DSS-induced colitis, demonstrating greater body weight loss, increased mortality, faster onset of rectal bleeding, shortened colon length, and increased CD11b- or Gr-1-positive myeloid cells in the colon compared with wild-type (WT) mice. These parameters were restored to, if not better than, the WT levels when we examined hMRP8 Hif-1a KO mice upon 5% DSS feeding. hMRP8 Hif-2a KO mice, on the other hand, exhibited a similar degree of DSS-induced colitis to that of WT mice. Lastly, when DSS was given together with azoxymethane to induce tumorigenesis in the colon, we found that hMRP8 Hif-1a KO mice exhibited comparable levels of colorectal tumors to those of WT mice, indicating that HIF-1α in myeloid cells is dispensable for tumorigenesis. Collectively, our results suggest that HIF-1α activation in myeloid cells critically regulates IBD progression.

Keywords: Colitis; Dextran sodium sulfate; Hypoxia-inducible factor; Myeloid cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Antigens, Ly / metabolism
  • Azoxymethane
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • CD11b Antigen / metabolism
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Colitis / chemically induced*
  • Colitis / metabolism
  • Colitis / pathology*
  • Colitis / prevention & control
  • Colon / metabolism
  • Colon / pathology
  • Dextran Sulfate
  • Disease Progression*
  • Disease Susceptibility
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Mice
  • Mice, Knockout
  • Myeloid Cells / metabolism*
  • Myeloid Cells / pathology*
  • Promoter Regions, Genetic / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism


  • ABCC11 protein, human
  • ATP-Binding Cassette Transporters
  • Antigens, Ly
  • Basic Helix-Loop-Helix Transcription Factors
  • CD11b Antigen
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Ly6G antigen, mouse
  • Tumor Necrosis Factor-alpha
  • endothelial PAS domain-containing protein 1
  • Dextran Sulfate
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, mouse
  • Azoxymethane