HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection

Leishmanial skin lesions are characterized by inflammatory hypoxia alongside the activation of hypoxia-inducible factors, HIF-1 alpha and HIF-2 alpha, and subsequent expression of the HIF-alpha target VEGF-A during Leishmania major infection. However, the factors responsible for HIF-alpha activation are not known. We hypothesize that hypoxia and proinflammatory stimuli contribute to HIF-alpha activation during infection. RNA-Seq of leishmanial lesions revealed that transcripts associated with HIF-1 alpha signaling were induced. To determine whether hypoxia contributes to HIF-alpha activation, we followed the fate of myeloid cells infiltrating from the blood and into hypoxic lesions. Recruited myeloid cells experienced hypoxia when they entered inflamed lesions, and the length of time in lesions increased their hypoxic signature. To determine whether proinflammatory stimuli in the inflamed tissue can also influence HIF-alpha activation, we subjected macrophages to various proinflammatory stimuli and measured VEGF-A. While parasites alone did not induce VEGF-A, and proinflammatory stimuli only modestly induced VEGF-A, HIF-alpha stabilization increased VEGF-A during infection. HIF-alpha stabilization did not impact parasite entry, growth, or killing. Conversely, the absence of ARNT/HIF-alpha signaling enhanced parasite internalization. Altogether, these findings suggest that HIF-alpha is active during infection, and while macrophage HIF-alpha activation promotes lymphatic remodeling through VEGF-A production, HIF-alpha activation does not impact parasite internalization or control.

Automated summary

Leishmanial skin lesions are characterized by inflammatory hypoxia and the activation of hypoxia-inducible factors. The factors responsible for HIF-alpha activation during infection are not fully known, but both hypoxia and proinflammatory stimuli may contribute to this. HIF-alpha activation in macrophages promotes lymphatic remodeling through VEGF-A production, but has no impact on parasite internalization or control.