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

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1584
Author(s):  
Manjunath Bettadapura ◽  
Hayden Roys ◽  
Anne Bowlin ◽  
Gopinath Venugopal ◽  
Charity L. Washam ◽  
...  

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.

Author(s):  
Manjunath Bettadapura ◽  
Hayden Roys ◽  
Anne Bowlin ◽  
Gopinath Venugopal ◽  
Charity L. Washam ◽  
...  

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


2007 ◽  
Vol 56 (3) ◽  
pp. 231-234 ◽  
Author(s):  
Yasuyuki Goto ◽  
Chizu Sanjoba ◽  
Nana Arakaki ◽  
Masaaki Okamoto ◽  
Keiichi Saeki ◽  
...  

2010 ◽  
Vol 83 (6) ◽  
pp. 1295-1300 ◽  
Author(s):  
Pieter-Paul van Thiel ◽  
Wendy F. van der Meide ◽  
Allard van der Sluis ◽  
Jimmy E. Zeegelaar ◽  
Aldert Bart ◽  
...  

2013 ◽  
Vol 95 (2) ◽  
pp. 347-355 ◽  
Author(s):  
Wânia F. Pereira-Manfro ◽  
Flávia L. Ribeiro-Gomes ◽  
Alessandra Almeida Filardy ◽  
Natália S. Vellozo ◽  
Landi V. C. Guillermo ◽  
...  

2011 ◽  
Vol 7 (9) ◽  
pp. 1220-1229 ◽  
Author(s):  
Guillermo Elizondo ◽  
Miriam Rodríguez-Sosa ◽  
Elizabet Estrada-Muñiz ◽  
Frank J. Gonzalez ◽  
Libia Vega

2009 ◽  
Vol 104 (6) ◽  
pp. 918-922 ◽  
Author(s):  
Silvia Dantas Cangussú ◽  
Carolina Carvalho de Souza ◽  
Camila França Campos ◽  
Leda Quercia Vieira ◽  
Luís Carlos Crocco Afonso ◽  
...  

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