title: HIF-1α is a negative regulator of plasmacytoid DC development in vitro and in vivo.
abstract: Hypoxia-inducible factors (HIFs) regulate hematopoiesis in the embryo and maintain hematopoietic stem cell function in the adult. How hypoxia and HIFs contribute to hematopoietic lineage differentiation in the adult is ill defined. Here we provide evidence that HIF-1 limits differentiation of precursors into plasmacytoid dendritic cells (pDCs). Low oxygen up-regulated inhibitor of DNA binding 2 (ID2) and suppressed Flt3-L-induced differentiation of bone marrow cells to pDCs in wild-type but not HIF-1α(fl/fl) LysM-Cre bone marrow cells. Moreover, pDC differentiated normally in hypoxic ID2(-/-) bone marrow cultures. Finally, we observed elevated pDC frequencies in bone marrow, blood, and spleen of HIF-1α(fl/fl) LysM-Cre and ID2(-/-), but not HIF-2α(fl/fl) LysM-Cre mice. Our data indicate that the low oxygen content in the bone marrow might limit pDC development. This might be an environmental mechanism to restrict the numbers of these potentially autoreactive cells.
authors.affiliation: Institute of Biochemistry I, Goethe-University Frankfurt, Frankfurt, Germany. weigert@zbc.kgu.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weichand
authors.forename: Divya
authors.initials: D
authors.lastname: Sekar
authors.forename: Weixiao
authors.initials: W
authors.lastname: Sha
authors.forename: Christina
authors.initials: C
authors.lastname: Hahn
authors.forename: Javier
authors.initials: J
authors.lastname: Mora
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ley
authors.forename: Silke
authors.initials: S
authors.lastname: Essler
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dehne
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D001853:Bone Marrow / Q000473:pathology*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006413:Hematopoietic System / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D066298:In Vitro Techniques; D051797:Inhibitor of Differentiation Protein 2 / Q000502:physiology; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051797:Inhibitor of Differentiation Protein 2; D019426:Integrases; D010100:Oxygen; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C497452:Idb2 protein, mouse; C045073:Cre recombinase