Defective neutrophil-derived exosomes facilitate macrophage activation through miR-122-5p in Behçet’s disease

Xin Yu, Menghao Zhang, Na Kang, Chaoran Li, Zhimian Wang, Yiyuan Ao, Lu Li, Xiao’ou Wang, Yeling Liu, Lidan Zhao, Li Wang, Min Shen, Jinjing Liu, Yan Zhao, Fengchun Zhang, Hua Chen () and Wenjie Zheng ()
Additional contact information
Xin Yu: Ministry of Science & Technology
Menghao Zhang: Ministry of Science & Technology
Na Kang: Tsinghua University
Chaoran Li: Ministry of Science & Technology
Zhimian Wang: Ministry of Science & Technology
Yiyuan Ao: Ministry of Science & Technology
Lu Li: Chinese Academy of Medical Sciences & Peking Union Medical College
Xiao’ou Wang: Ministry of Science & Technology
Yeling Liu: Ministry of Science & Technology
Lidan Zhao: Ministry of Science & Technology
Li Wang: Ministry of Science & Technology
Min Shen: Ministry of Science & Technology
Jinjing Liu: Ministry of Science & Technology
Yan Zhao: Ministry of Science & Technology
Fengchun Zhang: Ministry of Science & Technology
Hua Chen: Ministry of Science & Technology
Wenjie Zheng: Ministry of Science & Technology

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63348-8

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