Manuel A. Sánchez-García, Pranvera Sadiku, Brian M. Ortmann, Niek Wit, Yutaka Negishi, Patrícia Coelho, Ailiang Zhang, Chinmayi Pednekar, Andrew J.M. Howden, David Griffith, Rachel Seear, Jessica D. Kindrick, Janine Mengede, George Cooper, Tyler Morrison, Emily Watts, Benjamin T. Shimeld, Leila Reyes, Ananda S. Mirchandani, Simone Arienti, Xiang Xu, Alexander Thomson, Alejandro J. Brenes, H. Turton, Rebecca Dowey, Rebecca C Hull, Hazel Davidson‐Smith, Amy McLaren, Andrew Deans, Gourab Choudhury, Katherine Doverman, David Hope, Oliver Vick, Alastair Woodhead, Isla Petrie, Suzanne Green, Nina M. Rzechorzek, Lance Turtle, Peter Openshaw, Malcolm G. Semple, the PHOSP-COVID Study Collaborative Group, Duncan Sproul, J. Kenneth Baillie, A. A. Roger Thompson, David R. Mole, Alex von Kriegsheim, Moira K. B. Whyte, Musa M. Mhlanga, James A. Nathan, Sarah R. Walmsley
The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3-6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors.