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

Hypoxia-inducible factor-1 alpha (HIF-1 alpha), which accumulates in mammalian host organisms during infection, supports the defense against microbial pathogens. However, whether and to what extent HIF-1 alpha expressed by myeloid cells contributes to the innate immune response against Leishmania major parasites is unknown. We observed that Leishmania-infected humans and L. majorinfected C57BL/6 mice exhibited substantial amounts of HIF-1 alpha in acute cutaneous lesions. In vitro, HIF-1 alpha was required for leishmanicidal activity and high-level NO production by IFN-gamma/LPS-activated macrophages. Mice deficient for HIF-1 alpha 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-1 alpha is required for optimal innate leishmanicidal immune responses and, thereby, contributes to the cure of cutaneous leishmaniasis.