Fleming Kathryn, Burley Kate, Ponce-Garcia Fernando, Akbari Parsa, Naveh Claire, Rice Chris, Zakrzewski Przemysław, Gibbs Willem, Groves Sarah, Cela Drinalda, Papayannopoulos Venizelos, Harbort Christopher J, Mumford Andrew, Amulic Borko
School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Wort's Causeway, Cambridge, UK.
iScience. 2025 Jul 7;28(8):113072. doi: 10.1016/j.isci.2025.113072. eCollection 2025 Aug 15.
Neutrophils are essential immune cells loaded with cytosolic granules that contain potent antimicrobial and immunostimulatory molecules. Alterations of neutrophil granule contents are associated with immunodeficiency and hyperinflammation. Identification of regulators of granule development can aid in understanding of neutrophil-driven pathologies. Here, we perform a systematic prioritization of genetic variants associated with neutrophil cytometric side scatter (SSC), a proxy for granularity, identified in a genome-wide association study (GWAS) of blood parameters in healthy individuals. We show that triangulation of GWAS data with epigenetic and eQTL data identifies previously unknown factors regulating neutrophil granularity. We validate this approach using cellular and animal models to confirm that cyclin dependent kinase 6 (encoded by ) regulates neutrophil granule development. CDK6 specifically regulates the abundance of primary granules without affecting neutrophil maturation. Our approach demonstrates the utility of cell counter-derived SSC data paired with genomics as a tool to investigate neutrophil development and function.
中性粒细胞是重要的免疫细胞，其胞质颗粒中含有强效抗菌和免疫刺激分子。中性粒细胞颗粒内容物的改变与免疫缺陷和过度炎症相关。鉴定颗粒发育的调节因子有助于理解中性粒细胞驱动的病理过程。在此，我们对与中性粒细胞流式细胞术侧向散射（SSC）相关的遗传变异进行了系统的优先级排序，SSC是颗粒度的一个指标，在健康个体血液参数的全基因组关联研究（GWAS）中被鉴定出来。我们表明，将GWAS数据与表观遗传和eQTL数据进行三角测量可识别出先前未知的调节中性粒细胞颗粒度的因素。我们使用细胞和动物模型验证了这种方法，以确认细胞周期蛋白依赖性激酶6（由 编码）调节中性粒细胞颗粒发育。CDK6特异性调节初级颗粒的丰度，而不影响中性粒细胞成熟。我们的方法证明了细胞计数器衍生的SSC数据与基因组学相结合作为研究中性粒细胞发育和功能的工具的实用性。
