Wang Qingfeng, Ma Junfeng, Gong Yuxing, Zhu Lifu, Tang Huanyu, Ye Xingsheng, Su Guannan, Huang Fanfan, Tan Shiyao, Zuo Xianbo, Gao Yuan, Yang Peizeng
The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing, China.
Cell Discov. 2024 May 4;10(1):47. doi: 10.1038/s41421-024-00671-2.
Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-α responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Behçet's uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases.
中性粒细胞是循环系统中最早对损伤作出反应的最丰富的免疫细胞。尽管相关证据表明中性粒细胞的差异可能与炎症性疾病的性别特异性易感性有关，但其机制联系仍不明确。在这里，我们在单细胞分辨率下确定了正常和自身炎症条件下中性粒细胞组成中广泛的性别特异性异质性。通过结合单细胞RNA测序分析、中性粒细胞特异性基因敲除和转移实验，我们发现两个非常规（干扰素-α反应性和T细胞调节性）中性粒细胞亚群的失调导致自身炎症性白塞氏葡萄膜炎男性发病率更高、病情更严重且预后更差。全基因组关联研究（GWAS）和外泌体研究表明，遗传因素和循环外泌体对非常规中性粒细胞亚群的男性特异性负面影响导致男性对疾病的特异性易感性。总体而言，我们的研究结果确定了性别特异性不同的中性粒细胞亚群，并突出了非常规中性粒细胞亚群作为限制炎症性疾病的性别特异性治疗靶点。
