Yu Xin, Zhang Menghao, Kang Na, Li Chaoran, Wang Zhimian, Ao Yiyuan, Li Lu, Wang Xiao'ou, Liu Yeling, Zhao Lidan, Wang Li, Shen Min, Liu Jinjing, Zhao Yan, Zhang Fengchun, Chen Hua, Zheng Wenjie
Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College; National Clinical Research Center for Dermatologic and Immunologic Diseases, Ministry of Science & Technology, Beijing, China.
Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
Nat Commun. 2025 Sep 2;16(1):8186. doi: 10.1038/s41467-025-63348-8.
Behçet's disease (BD) is a life-threatening systemic vasculitis characterized by polymorphonuclear neutrophils (PMN) and macrophage activation. However, the interaction of PMN and macrophages remains elusive. To elucidate the potential dysregulation of BD PMN exosomes on macrophage activation, PMN exosomes from both BD patients and healthy controls are isolated, quantified and incubated with macrophages. We find that BD PMN exosomes are decreased and negatively correlated with C-reactive protein (CRP). PMN exosomes can suppress IL-6, TNF, CD80 and CD86 expressions on macrophages, which are attenuated in BD PMN exosomes. In addition, by miRNA sequencing of PMN exosomes, RNA sequencing of miRNA-transfected macrophages, and dual luciferase reporter assay validation of the miRNA target, we find that miR-122-5p is decreased in BD PMN exosomes, targeting IRF5, suppressing TLR4 signaling and IFN-β autocrine, eventually downregulating macrophage activation. Our study illustrates that BD PMN exosomes are decreased in both quantity and miR-122-5p, which impairs the potential immunoregulatory effects on macrophages through degrading IRF5 and suppressing IFN-β autocrine, shedding light on the interaction mechanism between PMN and macrophages.
白塞病（BD）是一种危及生命的全身性血管炎，其特征为多形核中性粒细胞（PMN）和巨噬细胞活化。然而，PMN与巨噬细胞之间的相互作用仍不清楚。为了阐明BD患者PMN外泌体对巨噬细胞活化的潜在失调作用，我们分离、定量了BD患者和健康对照者的PMN外泌体，并将其与巨噬细胞一起孵育。我们发现BD患者的PMN外泌体减少，且与C反应蛋白（CRP）呈负相关。PMN外泌体可抑制巨噬细胞上IL-6、TNF、CD80和CD86的表达，而BD患者的PMN外泌体中这些抑制作用减弱。此外，通过对PMN外泌体进行miRNA测序、对转染miRNA的巨噬细胞进行RNA测序以及对miRNA靶标进行双荧光素酶报告基因检测验证，我们发现BD患者的PMN外泌体中miR-122-5p减少，其靶向IRF5，抑制TLR4信号传导和IFN-β自分泌，最终下调巨噬细胞活化。我们的研究表明，BD患者的PMN外泌体在数量和miR-122-5p方面均减少，这通过降解IRF5和抑制IFN-β自分泌损害了对巨噬细胞的潜在免疫调节作用，为PMN与巨噬细胞之间的相互作用机制提供了新的线索。
