Williams Jordan E, Mauya Zannatul, Walkup Virginia, Adderley Shaquria, Evans Colin, Wilson Kiesha
Department of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, Columbia, SC 29209, USA.
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29209, USA.
Cells. 2025 Jul 25;14(15):1151. doi: 10.3390/cells14151151.
Acute respiratory distress syndrome (ARDS) is an inflammatory pulmonary condition that remains at alarming rates of fatality, with neutrophils playing a vital role in its pathogenesis. Beyond their classical antimicrobial functions, neutrophils contribute to pulmonary injury via the release of reactive oxygen species, proteolytic enzymes, and neutrophil extracellular traps (NETs). To identify targets for treatment, it was found that epigenetic mechanisms, including histone modifications, hypomethylation, hypermethylation, and non-coding RNAs, regulate neutrophil phenotypic plasticity, survival, and inflammatory potential. It has been identified that neutrophils in ARDS patients exhibit abnormal methylation patterns and are associated with altered gene expression and prolonged neutrophil activation, thereby contributing to sustained inflammation. Histone citrullination, particularly via PAD4, facilitates NETosis, while histone acetylation status modulates chromatin accessibility and inflammatory gene expression. MicroRNAs have also been shown to regulate neutrophil activity, with miR-223 and miR-146a potentially being biomarkers and therapeutic targets. Neutrophil heterogeneity, as evidenced by distinct subsets such as low-density neutrophils (LDNs), varies across ARDS etiologies, including COVID-19. Single-cell RNA sequencing analyses, including the use of trajectory analysis, have revealed transcriptionally distinct neutrophil clusters with differential activation states. These studies support the use of epigenetic inhibitors, including PAD4, HDAC, and DNMT modulators, in therapeutic intervention. While the field has been enlightened with new findings, challenges in translational application remain an issue due to species differences, lack of stratification tools, and heterogeneity in ARDS presentation. This review describes how targeting neutrophil epigenetic regulators could help regulate hyperinflammation, making epigenetic modulation a promising area for precision therapeutics in ARDS.
急性呼吸窘迫综合征（ARDS）是一种炎症性肺部疾病，其死亡率一直居高不下，中性粒细胞在其发病机制中起着至关重要的作用。除了其经典的抗菌功能外，中性粒细胞还通过释放活性氧、蛋白水解酶和中性粒细胞胞外陷阱（NETs）导致肺损伤。为了确定治疗靶点，研究发现表观遗传机制，包括组蛋白修饰、低甲基化、高甲基化和非编码RNA，调节中性粒细胞的表型可塑性、存活和炎症潜能。已确定ARDS患者的中性粒细胞表现出异常的甲基化模式，并与基因表达改变和中性粒细胞活化延长有关，从而导致持续炎症。组蛋白瓜氨酸化，特别是通过肽基精氨酸脱亚氨酶4（PAD4），促进NETosis，而组蛋白乙酰化状态调节染色质可及性和炎症基因表达。微小RNA也被证明可调节中性粒细胞活性，其中miR-223和miR-146a可能是生物标志物和治疗靶点。中性粒细胞异质性，如低密度中性粒细胞（LDNs）等不同亚群所证明的，在包括2019冠状病毒病（COVID-19）在内的ARDS病因中各不相同。单细胞RNA测序分析，包括使用轨迹分析，揭示了具有不同激活状态的转录上不同的中性粒细胞簇。这些研究支持在治疗干预中使用表观遗传抑制剂，包括PAD4、组蛋白去乙酰化酶（HDAC）和DNA甲基转移酶（DNMT）调节剂。虽然该领域有了新的发现，但由于物种差异、缺乏分层工具以及ARDS表现的异质性，转化应用中的挑战仍然是一个问题。本综述描述了靶向中性粒细胞表观遗传调节剂如何有助于调节过度炎症，使表观遗传调节成为ARDS精准治疗的一个有前景的领域。
