The human body hates not getting enough oxygen. Without it, confusion takes over, breathing and heart rate change, and skin turns blue. It turns out that the immune system feels the effects of not enough oxygen too. In a new study, researchers have shown that hypoxia also has long-term effects on successive generations of immune cells called neutrophils, which may impair the bodies’ ability to battle infection.1
Hypoxia Affects Neutrophils
Several serious medical conditions can result in hypoxia. Acute respiratory distress syndrome (ARDS) is a life-threatening illness that occurs when fluid leaks into the lungs. It can result from several conditions, including sepsis, trauma, or pneumonia. ARDS can lead to hypoxia as the lungs stop pumping oxygen around the body.
Research in mice had previously suggested that hypoxia could alter immune cells.2 Researchers at the University of Edinburgh, led by immunologist Sarah Walmsley, wanted to investigate whether the changes were mirrored in humans. They compared blood samples from 52 ARDS patients, both during their hospital stay and between three and six months later, with blood from healthy donors.
They found that ARDS survivors had impaired neutrophils, circulating first-line immune cells that battle infection. The patients were also more vulnerable to secondary bacterial infections.
A closer look at the neutrophils from ARDS patients showed that, months after the disease, their cells lost an epigenetic mark called H3K4me3. Previous studies have shown that this modification is important for neutrophils’ antimicrobial activity.3
The researchers next turned their focus to other ways people can experience hypoxia, such as in high-altitude environments. They took blood samples from 20 healthy volunteers before and after they spent a week at 4,775m altitude near the mountain Huayna Potosí in Bolivia. The volunteers’ neutrophils showed proteomic changes that mirrored those that affected the ARDS patients’ cells and a similar loss of H3K4me3 in genes linked to immune function.
How the Epigenetic Changes Begin
The team wanted to explore how the changes to the cells' epigenetic markers began. To do so, they turned to mouse models of hypoxia. They found that the loss of H3K4me3 began in neutrophil progenitor cells in the mice’s bone marrow. In these cells, hypoxia induced a process called histone clipping, which cuts off part of the proteins that cells use to package DNA. This severance also reduced H3K4me3 levels.
The team wrote that the findings reveal more about how low-oxygen environments alter the immune system. They added that their research may provide helpful information for treating conditions in which neutrophil function contributes to pathology.
“Recognizing that low oxygen levels have a long-lasting effect on how early responder immune cells read their genetic code is important because it explains why these cells are less good at controlling infection many months after a severe respiratory illness. The [discovery] opens up new ways to think about treating long-term immune dysfunction and improve infection defenses,” said Manuel Alejandro Sanchez Garcia, a study coauthor and immunologist at the University of Edinburgh, in a press release.
- Sanchez-Garcia MA, et al. Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity. Nat Immunol. 2025:1-13.
- Mirchandani AS, et al. Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation. Nat Immunol. 2022;23(6):927-939.
- Moorlag SJCFM et al. BCG vaccination induces long-term functional reprogramming of human neutrophils. Cell Rep. 2020;33(7):108387.
