title: Myeloid cell HIF-1α regulates asthma airway resistance and eosinophil function.
abstract: Hypoxia-inducible factor (HIF)-1α is a master regulator of inflammatory activities of myeloid cells, including neutrophils and macrophages. These studies examine the role of myeloid cell HIF-1α in regulating asthma induction and pathogenesis, and for the first time, evaluate the roles of HIF-1α and HIF-2α in the chemotactic properties of eosinophils, the myeloid cells most associated with asthma. Wild-type (WT) and myeloid cell-specific HIF-1α knockout (KO) C57BL/6 mice were studied in an ovalbumin (OVA) model of asthma. Administration of the pharmacological HIF-1α antagonist YC-1 was used to corroborate findings from the genetic model. WT, HIF-1α, and HIF-2α KO eosinophils underwent in vitro chemotaxis assays. We found that deletion of HIF-1α in myeloid cells and systemic treatment with YC-1 during asthma induction decreased airway hyperresponsiveness (AHR). Deletion of HIF-1α in myeloid cells in OVA-induced asthma also reduced eosinophil infiltration, goblet cell hyperplasia, and levels of cytokines IL-4, IL-5, and IL-13 in the lung. HIF-1α inhibition with YC-1 during asthma induction decreased eosinophilia in bronchoalveolar lavage, lung parenchyma, and blood, as well as decreased total lung inflammation, IL-5, and serum OVA-specific IgE levels. Deletion of HIF-1α in eosinophils decreased their chemotaxis, while deletion of the isoform HIF-2α led to increased chemotaxis. This work demonstrates that HIF-1α in myeloid cells plays a role in asthma pathogenesis, particularly in AHR development. Additionally, treatment with HIF-1α inhibitors during asthma induction decreases AHR and eosinophilia. Finally, we show that HIF-1α and HIF-2α regulate eosinophil migration in opposing ways.
authors.affiliation: Pulmonary Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA. lcrotty@ucsd.edu
authors.forename: Laura E
authors.initials: LE
authors.lastname: Crotty Alexander
authors.forename: Kathryn
authors.initials: K
authors.lastname: Akong-Moore
authors.forename: Stephanie
authors.initials: S
authors.lastname: Feldstein
authors.forename: Per
authors.initials: P
authors.lastname: Johansson
authors.forename: Anh
authors.initials: A
authors.lastname: Nguyen
authors.forename: Elisa K
authors.initials: EK
authors.lastname: McEachern
authors.forename: Shari
authors.initials: S
authors.lastname: Nicatia
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Cowburn
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.forename: Jae Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: Hart
authors.initials: H
authors.lastname: Isaacs
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: David H
authors.initials: DH
authors.lastname: Broide
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000403:Airway Resistance / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004804:Eosinophils / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000276:immunology / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D007191:Indazoles / Q000494:pharmacology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D015848:Interleukin-5 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin; D015398:Signal Transduction; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D018793:Interleukin-13; D015847:Interleukin-4; D015848:Interleukin-5; D010047:Ovalbumin; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole