Prolonged exposure to hypoxia induces an autophagy-like cell survival program in human neutrophils. Issue 6 (14th August 2019)

• Record Type: Journal Article
• Authors: Talla, Usharani; Bozonet, Stephanie M; Parker, Heather A; Hampton, Mark B; Vissers, Margreet C M
• Is Part Of: Journal of leukocyte biology. Volume 106:Issue 6(2019)
• Page Start: 1367
• Page End: 1379
• Publication Date: 2019-08-14
• Subjects: autophagosomes -- bacterial killing -- hypoxia -- myeloperoxidase -- necrosis -- neutrophil apoptosis -- neutrophil viability -- respiratory burst; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1002/JLB.4A0319-079RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract: Neutrophils contribute to low oxygen availability at inflammatory sites through the generation of reactive oxidants. They are also functionally affected by hypoxia, which delays neutrophil apoptosis. However, the eventual fate of neutrophils in hypoxic conditions is unknown and this is important for their effective clearance and the resolution of inflammation. We have monitored the survival and function of normal human neutrophils exposed to hypoxia over a 48 h period. Apoptosis was delayed, and the cells remained intact even at 48 h. However, hypoxia promoted significant changes in neutrophil morphology with the appearance of many new cytoplasmic vesicles, often containing cell material, within 5 hours of exposure to low O2 . This coincided with an increase in LC3B-II expression, indicative of autophagosome formation and an autophagy-like process. In hypoxic conditions, neutrophils preferentially lost myeloperoxidase, a marker of azurophil granules. Short-term (2 h) hypoxic exposure resulted in sustained potential to generate superoxide when O2 was restored, but the capacity for oxidant production was lost with longer periods of hypoxia. Phagocytic ability was unchanged by hypoxia, and bacterial killing by neutrophils in both normoxic and hypoxic conditions was substantially diminished after 24 hours. However, pre-exposure to hypoxia resulted in an enhanced ability to kill bacteria by oxidant-independent mechanisms. Our data provide the first evidence for hypoxia as a driver of neutrophil autophagy that can influence the function and ultimate fate of these cells, including their eventual clearance and the resolution of inflammation. Graphical Abstract: Neutrophils undergo apoptosis in normoxic conditions, with loss of function, whereas in hypoxia there are autophagy-like morphological changes with mixed impact on survival and function.