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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-1α and HIF-2α, and subsequent expression of the HIF-α target VEGF-A during Leishmania major infection. However, the factors responsible for HIF-α activation are not known. We...

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Autores principales: Bettadapura, Manjunath, Roys, Hayden, Bowlin, Anne, Venugopal, Gopinath, Washam, Charity L., Fry, Lucy, Murdock, Steven, Wanjala, Humphrey, Byrum, Stephanie D., Weinkopff, Tiffany
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8706659/
https://www.ncbi.nlm.nih.gov/pubmed/34959539
http://dx.doi.org/10.3390/pathogens10121584
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author Bettadapura, Manjunath
Roys, Hayden
Bowlin, Anne
Venugopal, Gopinath
Washam, Charity L.
Fry, Lucy
Murdock, Steven
Wanjala, Humphrey
Byrum, Stephanie D.
Weinkopff, Tiffany
author_facet Bettadapura, Manjunath
Roys, Hayden
Bowlin, Anne
Venugopal, Gopinath
Washam, Charity L.
Fry, Lucy
Murdock, Steven
Wanjala, Humphrey
Byrum, Stephanie D.
Weinkopff, Tiffany
author_sort Bettadapura, Manjunath
collection PubMed
description Leishmanial skin lesions are characterized by inflammatory hypoxia alongside the activation of hypoxia-inducible factors, HIF-1α and HIF-2α, and subsequent expression of the HIF-α target VEGF-A during Leishmania major 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.
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spelling pubmed-87066592021-12-25 HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection Bettadapura, Manjunath Roys, Hayden Bowlin, Anne Venugopal, Gopinath Washam, Charity L. Fry, Lucy Murdock, Steven Wanjala, Humphrey Byrum, Stephanie D. Weinkopff, Tiffany Pathogens Article Leishmanial skin lesions are characterized by inflammatory hypoxia alongside the activation of hypoxia-inducible factors, HIF-1α and HIF-2α, and subsequent expression of the HIF-α target VEGF-A during Leishmania major 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. MDPI 2021-12-06 /pmc/articles/PMC8706659/ /pubmed/34959539 http://dx.doi.org/10.3390/pathogens10121584 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bettadapura, Manjunath
Roys, Hayden
Bowlin, Anne
Venugopal, Gopinath
Washam, Charity L.
Fry, Lucy
Murdock, Steven
Wanjala, Humphrey
Byrum, Stephanie D.
Weinkopff, Tiffany
HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection
title HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection
title_full HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection
title_fullStr HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection
title_full_unstemmed HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection
title_short HIF-α Activation Impacts Macrophage Function during Murine Leishmania major Infection
title_sort hif-α activation impacts macrophage function during murine leishmania major infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8706659/
https://www.ncbi.nlm.nih.gov/pubmed/34959539
http://dx.doi.org/10.3390/pathogens10121584
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