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ROS Activated NETosis of Bone Marrow CD55+ Intermediate Mature Neutrophils Through HIF1α-PADI4 Pathway to Initiate
Yutong Guo1, Shengjie Cui2, Xi Wen1
1Department of Orthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices& Beijing Key Laboratory of Digital Stomatology & NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory For Dental Materials, Beijing, P. R. China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 8, 2026
Summary
Neutrophil NETosis in bone marrow drives bone aging by inducing senescence in bone marrow stromal cells. Clearing NETs (neutrophil extracellular traps) ameliorates aging, revealing a target for osteoporosis treatment.
Area of Science:
- Immunology
- Gerontology
- Cell Biology
Background:
- Neutrophil NETosis is dysregulated in aging.
- The role of bone marrow NETosis in bone aging is unclear.
- Neutrophil heterogeneity and bone marrow inflammation's impact on NETosis need investigation.
Purpose of the Study:
- Investigate NETosis in aging bone marrow.
- Determine the link between NETosis and bone aging.
- Identify mechanisms and cellular players regulating NETosis in bone aging.
Main Methods:
- Utilized senescence-accelerated mouse prone 6 (SAMP6) model.
- Assessed NETosis in bone marrow neutrophils.
- Employed scRNA-seq to identify neutrophil subsets.
- Performed cell transfer experiments.
- Investigated molecular pathways (ROS, HIF1α, PADI4).
Main Results:
- NETosis is highly activated in SAMP6 bone marrow.
- Released NETs induce bone marrow stromal cell (BMSC) senescence and impair osteogenesis.
- NET clearance ameliorates bone aging in SAMP6 mice.
- A CD55+ neutrophil subset with upregulated NETosis was identified and shown to induce bone aging.
- A pathway involving ROS, CD55, HIF1α, and PADI4 triggers NETosis.
Conclusions:
- Activated NETosis in CD55+ neutrophils initiates bone aging.
- A vicious cycle of inflammaging exists between immune dysregulation and cellular senescence in bone marrow.
- This study provides potential therapeutic targets for osteoporosis.
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