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 34 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.

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

“…Using an ovalbumin-induced (OVA-induced) asthma model, others have shown that myeloid HIF-1α deficiency reduces airway hyperresponsiveness and eosinophil infiltration. Furthermore, HIF-1α and HIF-2α directly regulate eosinophil chemotaxis in opposing ways (150). Therefore, the role of myeloid HIF-1α in airway diseases remains very complex, and varies in different experimental models.…”

Activation of the stress response in macrophages alters the M1/M2 balance by enhancing bacterial killing and IL-10 expression

“…Under sterile conditions alveolar (AMϕs) and peritoneal (PMϕs) were isolated by bronchoalveolar lavage and peritoneal lavage from naïve mice utilizing cold SF RPMI1640 medium, as described in detail previously [24][25][26]. In some studies, mice were subjected to thermal stress as previously described [27].…”

Hypoxia and the hypoxia-regulated transcription factor HIF-1α suppress the host defence of airway epithelial cells

“…[9][10][11][12][13][14][15][16][17] This suggests a distinct function of HIF in innate and adaptive immunity. 18 Myeloid HIF-1a, for instance, is essential in myeloid cell-mediated inflammation and enhances the bactericidal capacity of phagocytes. 13,19 In addition, mice deficient in HIF-1a in myeloid cells develop less severe LPS-induced sepsis.…”