Myeloid cell HIF-1 alpha regulates asthma airway resistance and eosinophil function
2013 (English)In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 91, no 5, 637-644 p.Article in journal (Refereed) Published
Hypoxia-inducible factor (HIF)-1 alpha is a master regulator of inflammatory activities of myeloid cells, including neutrophils and macrophages. These studies examine the role of myeloid cell HIF-1 alpha in regulating asthma induction and pathogenesis, and for the first time, evaluate the roles of HIF-1 alpha and HIF-2 alpha in the chemotactic properties of eosinophils, the myeloid cells most associated with asthma. Wild-type (WT) and myeloid cell-specific HIF-1 alpha knockout (KO) C57BL/6 mice were studied in an ovalbumin (OVA) model of asthma. Administration of the pharmacological HIF-1 alpha antagonist YC-1 was used to corroborate findings from the genetic model. WT, HIF-1 alpha, and HIF-2 alpha KO eosinophils underwent in vitro chemotaxis assays. We found that deletion of HIF-1 alpha in myeloid cells and systemic treatment with YC-1 during asthma induction decreased airway hyperresponsiveness (AHR). Deletion of HIF-1 alpha 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-1 alpha 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-1 alpha in eosinophils decreased their chemotaxis, while deletion of the isoform HIF-2 alpha led to increased chemotaxis. This work demonstrates that HIF-1 alpha in myeloid cells plays a role in asthma pathogenesis, particularly in AHR development. Additionally, treatment with HIF-1 alpha inhibitors during asthma induction decreases AHR and eosinophilia. Finally, we show that HIF-1 alpha and HIF-2 alpha regulate eosinophil migration in opposing ways.
Place, publisher, year, edition, pages
Springer Verlag (Germany) , 2013. Vol. 91, no 5, 637-644 p.
Hypoxia inducible factor (HIF)-1 alpha; Asthma; Allergic inflammation; Eosinophils; Chemotaxis; Airway hyperresponsiveness
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-96146DOI: 10.1007/s00109-012-0986-9ISI: 000318690500010OAI: oai:DiVA.org:liu-96146DiVA: diva2:640727