Details

Autor(en) / Beteiligte

• Thompson, A.A. Roger
• Elks, Philip M.
• Marriott, Helen M.
• Eamsamarng, Suttida
• Higgins, Kathryn R.
• Lewis, Amy
• Williams, Lynne
• Parmar, Selina
• Shaw, Gary
• McGrath, Emmet E.
• Formenti, Federico
• Van Eeden, Fredericus J.
• Kinnula, Vuokko L.
• Pugh, Christopher W.
• Sabroe, Ian
• Dockrell, David H.
• Chilvers, Edwin R.
• Robbins, Peter A.
• Percy, Melanie J.
• Simon, M. Celeste
• Johnson, Randall S.
• Renshaw, Stephen A.
• Whyte, Moira K.B.
• Walmsley, Sarah R.

Titel

Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish

Ist Teil von

• Blood, 2014-01, Vol.123 (3), p.366-376

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• Neutrophil lifespan and function are regulated by hypoxia via components of the hypoxia inducible factor (HIF)/von Hippel Lindau/hydroxylase pathway, including specific roles for HIF-1α and prolyl hydroxylase-3. HIF-2α has both distinct and overlapping biological roles with HIF-1α and has not previously been studied in the context of neutrophil biology. We investigated the role of HIF-2α in regulating key neutrophil functions. Human and murine peripheral blood neutrophils expressed HIF-2α, with expression up-regulated by acute and chronic inflammatory stimuli and in disease-associated inflammatory neutrophil. HIF2A gain-of-function mutations resulted in a reduction in neutrophil apoptosis both ex vivo, through the study of patient cells, and in vivo in a zebrafish tail injury model. In contrast, HIF-2α–deficient murine inflammatory neutrophils displayed increased sensitivity to nitrosative stress induced apoptosis ex vivo and increased neutrophil apoptosis in vivo, resulting in a reduction in neutrophilic inflammation and reduced tissue injury. Expression of HIF-2α was temporally dissociated from HIF-1α in vivo and predominated in the resolution phase of inflammation. These data support a critical and selective role for HIF-2α in persistence of neutrophilic inflammation and provide a platform to dissect the therapeutic utility of targeting HIF-2α in chronic inflammatory diseases. •Neutrophil lifespan is extended in patients with gain-of-function HIF2A mutations.•HIF-2α regulates in vivo neutrophil longevity and thus tissue inflammation and repair.