Myeloid Hypoxia-Inducible Factor 1α Prevents Airway Allergy in Mice Through Macrophage-Mediated Immunoregulation

Mucosal Immunol. 2013 May;6(3):485-97. doi: 10.1038/mi.2012.88. Epub 2012 Sep 12.

Abstract

Hypoxia-inducible factor (HIF) has important roles in promoting pro-inflammatory and bactericidal functions in myeloid cells. Conditional genetic ablation of its major subunit Hif1α in the myeloid lineage consequently results in decreased inflammatory responses in classical models of acute inflammation in mice. By contrast, we report here that mice conditionally deficient for Hif1α in myeloid cells display enhanced sensitivity to the development of airway allergy to experimental allergens and house-dust mite antigens. We support that upon allergen exposure, MyD88-dependent upregulation of Hif1α boosts the expression of the immunosuppressive cytokine interleukin (IL)-10 by lung interstitial macrophages (IMs). Hif1α-dependent IL-10 secretion is required for IMs to block allergen-induced dendritic cell activation and consequently for preventing the development of allergen-specific T-helper cell responses upon allergen exposure. Thus, this study supports that, in addition to its known pro-inflammatory activities, myeloid Hif1α possesses immunoregulatory functions implicated in the prevention of airway allergy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / genetics
  • Antigens, Dermatophagoides / immunology*
  • Dendritic Cells / immunology
  • Disease Models, Animal
  • Female
  • Immunosuppression
  • Interleukin-10 / immunology
  • Interleukin-10 / metabolism
  • Macrophages, Alveolar / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / immunology
  • Mixed Function Oxygenases / metabolism*
  • Myeloid Cells / immunology*
  • Myeloid Differentiation Factor 88 / metabolism
  • Organ Specificity / genetics
  • Pyroglyphidae / immunology
  • Respiratory Hypersensitivity / immunology*
  • Signal Transduction / genetics
  • T-Lymphocytes, Helper-Inducer / immunology

Substances

  • Antigens, Dermatophagoides
  • Myeloid Differentiation Factor 88
  • Interleukin-10
  • Mixed Function Oxygenases
  • factor inhibiting hypoxia-inducible factor 1, mouse