HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection
Manjunath Bettadapura, Hayden Roys, Anne K. Bowlin, Gopinath Venugopal, Charity L. Washam, Lucy Fry, Steven Murdock, Humphrey Wanjala, Stephanie D. Byrum, Tiffany Weinkopff
Abstract
infection. However, the factors responsible for HIF-α activation are not known. We hypothesize that hypoxia and proinflammatory stimuli contribute to HIF-α activation during infection. RNA-Seq of leishmanial lesions revealed that transcripts associated with HIF-1α signaling were induced. To determine whether hypoxia contributes to HIF-α 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-α 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-α stabilization increased VEGF-A during infection. HIF-α stabilization did not impact parasite entry, growth, or killing. Conversely, the absence of ARNT/HIF-α signaling enhanced parasite internalization. Altogether, these findings suggest that HIF-α is active during infection, and while macrophage HIF-α activation promotes lymphatic remodeling through VEGF-A production, HIF-α activation does not impact parasite internalization or control.