Myeloid cell HIF-1α regulates asthma airway resistance and eosinophil function.

Autor: Crotty Alexander LE; Pulmonary Critical Care Section, Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA. lcrotty@ucsd.edu, Akong-Moore K, Feldstein S, Johansson P, Nguyen A, McEachern EK, Nicatia S, Cowburn AS, Olson J, Cho JY, Isaacs H Jr, Johnson RS, Broide DH, Nizet V
Jazyk: angličtina
Zdroj: Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2013 May; Vol. 91 (5), pp. 637-44. Date of Electronic Publication: 2012 Dec 19.
DOI: 10.1007/s00109-012-0986-9
Abstrakt: 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.
Databáze: MEDLINE
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