title: Hypoxia inducible factors are dispensable for myeloid cell migration into the inflamed mouse eye.
abstract: Hypoxia inducible factors (HIFs) are ubiquitously expressed transcription factors important for cell homeostasis during dynamic oxygen levels. Myeloid specific HIFs are crucial for aspects of myeloid cell function, including their ability to migrate into inflamed tissues during autoimmune disease. This contrasts with the concept that accumulation of myeloid cells at ischemic and hypoxic sites results from a lack of chemotactic responsiveness. Here we seek to address the role of HIFs in myeloid trafficking during inflammation in a mouse model of human uveitis. We show using mice with myeloid-specific Cre-deletion of HIFs that myeloid HIFs are dispensable for leukocyte migration into the inflamed eye. Myeloid-specific deletion of Hif1a, Epas1, or both together, had no impact on the number of myeloid cells migrating into the eye. Additionally, stabilization of HIF pathways via deletion of Vhl in myeloid cells had no impact on myeloid trafficking into the inflamed eye. Finally, we chemically induce hypoxemia via hemolytic anemia resulting in HIF stabilization within circulating leukocytes to demonstrate the dispensable role of HIFs in myeloid cell migration into the inflamed eye. These data suggest, contrary to previous reports, that HIF pathways in myeloid cells during inflammation and hypoxia are dispensable for myeloid cell tissue trafficking.
authors.affiliation: UCL Institute of Ophthalmology, Genetics department, London, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gardner
authors.affiliation: UCL Institute of Ophthalmology, Genetics department, London, United Kingdom.
authors.forename: Sidath E
authors.initials: SE
authors.lastname: Liyanage
authors.affiliation: UCL Institute of Ophthalmology, Genetics department, London, United Kingdom.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cristante
authors.affiliation: UCL Institute of Ophthalmology, Genetics department, London, United Kingdom.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Sampson
authors.affiliation: UCL Institute of Ophthalmology, Genetics department, London, United Kingdom.|NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, United Kingdom.|University of Bristol, Academic Unit of Ophthalmology, Bristol, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
authors.affiliation: UCL Institute of Ophthalmology, Genetics department, London, United Kingdom.|NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, United Kingdom.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
authors.affiliation: UCL Institute of Ophthalmology, Genetics department, London, United Kingdom.|NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, United Kingdom.
authors.forename: James W
authors.initials: JW
authors.lastname: Bainbridge
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism* / Q000502:physiology; D014605:Uveitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C494469:VHL protein, mouse