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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8706659 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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