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

Abstract

Key Points 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.

Hypoxic regulation of neutrophil function and consequences for Staphylococcus aureus infection

“…Notably, deficiency of HIF-2a impairs neither neutrophil survival in hypoxia nor key neutrophil functions, suggesting that HIF-2a plays a less prominent role in the control of hypoxic neutrophil responses. Nonetheless, HIF-2a does appear to regulate neutrophil lifespan in the context of inflammation; lower expression of the antioxidant enzyme catalase in HIF-2a deficient neutrophils compared to wildtype cells was associated with increased apoptosis in response to nitrosative stress, and enhanced inflammation resolution in a model of acute lung injury [35].…”

“…Of the 3 known HIF-a subunits, neutrophils express both HIF-1a and HIF-2a mRNA, and both proteins are stabilized in hypoxia and when these cells are exposed to inflammatory stimuli, such as LPS and streptococci [35]. HIF-1a and HIF2a regulate distinct but overlapping target gene sets, with HIF1a having a greater impact upon immediate metabolic targets.…”

Hypoxia-dependent regulation of inflammatory pathways in immune cells

“…HIF-1 promotes neutrophil survival and bactericidal activity (33,34). Similarly, HIF-2 appears to support neutrophilic inflammation through the promotion of cell survival (35). Of interest, HIF-2 expression in neutrophils is elevated in patients with inflammatory disease (35).…”

“…Similarly, HIF-2 appears to support neutrophilic inflammation through the promotion of cell survival (35). Of interest, HIF-2 expression in neutrophils is elevated in patients with inflammatory disease (35). Therefore, in the context of inflammation, HIF-1/2 activation in neutrophils can be considered to be largely proinflammatory.…”

Increased myeloid cell hypoxia-inducible factor-1 delays obliterative airway disease in the mouse

“…Previous studies showed that macrophages and neutrophils are able to express both HIF-1α and HIF-2α. 34,35 However, because the OAD development was significantly accelerated in mHIF-1α -/-recipients, one may assume that HIF-1 activity was the major contributor to the decreased OAD development in mVHL -/-recipients. In addition, Thompson et al 35 reported that HIF-2α regulates mainly key neutrophil functions, but we did not detect any significant difference in the number of MPO þ neutrophils between the groups at 3 or 10 days in our study.…”