爱丁堡大学Sarah R. Walmsley课题组取得一项新突破。他们的研究认为缺氧诱导中性粒细胞祖细胞组蛋白剪切和H3K4me3丢失，导致中性粒细胞免疫功能长期受损。相关论文发表在2025年10月28日出版的《自然—免疫学》杂志上。

课题组发现，从ARDS恢复后3-6个月的患者循环中性粒细胞效应功能持续受损，对继发感染的易感性增加。这些缺陷与对中性粒细胞活动至关重要的基因中活化组蛋白标记H3K4me3的广泛缺失有关。通过研究暴露于高海拔低氧血症的健康志愿者，研究组证明了缺氧本身就能抑制这种长期的中性粒细胞重编程。机制上，系统性缺氧的小鼠模型显示H3K4me3的持续缺失起源于骨髓内的preNeu和preNeu祖细胞，并与N端组蛋白3剪切有关，该剪切去除赖氨酸残基以进行甲基化。因此，该课题组研究人员提出了新的证据，表明全身性缺氧通过触发中性粒细胞祖细胞中的组蛋白3剪切和H3K4me3缺失，引发中性粒细胞免疫持续的适应性不良重编程。

据了解，急性呼吸窘迫综合征（ARDS）引起的全身性缺氧对短命先天免疫细胞功能的长期影响尚不清楚。

附：英文原文

Title: Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity

Author: Sanchez-Garcia, Manuel A., Sadiku, Pranvera, Ortmann, Brian M., Wit, Niek, Negishi, Yutaka, Coelho, Patricia, Zhang, Ailiang, Pednekar, Chinmayi, Howden, Andrew J. M., Griffith, David M., Seear, Rachel, Kindrick, Jessica D., Mengede, Janine, Cooper, George, Morrison, Tyler, Watts, Emily R., Shimeld, Benjamin T., Reyes, Leila, Mirchandani, Ananda S., Arienti, Simone, Xu, Xiang, Thomson, Alexander, Brenes, Alejandro J., Turton, Helena A., Dowey, Rebecca, Hull, Rebecca C., Davidson-Smith, Hazel, McLaren, Amy, Deans, Andrew, Choudhury, Gourab, Doverman, Katherine, Hope, David, Vick, Oliver, Woodhead, Alastair, Petrie, Isla, Green, Suzanne, Rzechorzek, Nina M., Turtle, Lance, Openshaw, Peter J. M., Semple, Malcolm G., Sproul, Duncan, Baillie, J. Kenneth, Thompson, Alfred A. R., Mole, David R., von Kriegsheim, Alex, Whyte, Moira K. B., Mhalanga, Musa M., Nathan, James A., Walmsley, Sarah R.

Issue&Volume: 2025-10-28

Abstract: 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.

DOI: 10.1038/s41590-025-02301-9

Source: https://www.nature.com/articles/s41590-025-02301-9