Myeloid Cell-Derived HIF-1α Promotes Control of Leishmania major

J Immunol. 2016 Nov 15;197(10):4034-4041. doi: 10.4049/jimmunol.1601080. Epub 2016 Oct 17.

Abstract

Hypoxia-inducible factor-1α (HIF-1α), which accumulates in mammalian host organisms during infection, supports the defense against microbial pathogens. However, whether and to what extent HIF-1α expressed by myeloid cells contributes to the innate immune response against Leishmania major parasites is unknown. We observed that Leishmania-infected humans and L. major-infected C57BL/6 mice exhibited substantial amounts of HIF-1α in acute cutaneous lesions. In vitro, HIF-1α was required for leishmanicidal activity and high-level NO production by IFN-γ/LPS-activated macrophages. Mice deficient for HIF-1α in their myeloid cell compartment had a more severe clinical course of infection and increased parasite burden in the skin lesions compared with wild-type controls. These findings were paralleled by reduced expression of type 2 NO synthase by lesional CD11b+ cells. Together, these data illustrate that HIF-1α is required for optimal innate leishmanicidal immune responses and, thereby, contributes to the cure of cutaneous leishmaniasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / immunology*
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Immunity, Innate
  • Interferon-gamma / pharmacology
  • Leishmania major / immunology*
  • Leishmaniasis, Cutaneous / immunology*
  • Leishmaniasis, Cutaneous / parasitology
  • Leishmaniasis, Cutaneous / pathology
  • Lipopolysaccharides / immunology
  • Macrophages / immunology
  • Macrophages / parasitology
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells / metabolism*
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase / genetics
  • Parasite Load
  • Skin / parasitology*
  • Skin / pathology

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lipopolysaccharides
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase