2. Academic Validation
  3. The IL-1β/NETs/AIM2 axis participates in the formation of trauma-induced heterotopic ossification by orchestrating crosstalk between neutrophils and macrophages

The IL-1β/NETs/AIM2 axis participates in the formation of trauma-induced heterotopic ossification by orchestrating crosstalk between neutrophils and macrophages

  • J Adv Res. 2025 Jun 28:S2090-1232(25)00478-3. doi: 10.1016/j.jare.2025.06.069.
Zhengqiang Yuan 1,  Siyuan Yao 2,  Xiangyun Yao 1,  Chao Zhou 3,  Juehong Li 4,  Cunyi Fan 5
Affiliations

Affiliations

  • 1 Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 200233, PR China.
  • 2 Nursing Department, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China.
  • 3 Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 200233, PR China. Electronic address: zh2c0211@163.com.
  • 4 Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 200233, PR China. Electronic address: ljhong1116@163.com.
  • 5 Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 200233, PR China. Electronic address: cyfan@sjtu.edu.cn.
PMID: 40588026 DOI: 10.1016/j.jare.2025.06.069
Abstract

Introduction: The limitations of clinical treatment for trauma-induced heterotopic ossification (tHO) make it of great significance to fully study its pathogenesis for the treatment of this disease. The infiltration of inflammatory cells, as an important indicator of disease progression, should be further studied.

Objectives: In our study, we found that in the early stages of acute tendon injury, increased IL-1β can induce NETosis in neutrophils. Neutrophils and macrophages are early infiltrating cells in acute tendon injury, and their relationship has aroused our curiosity.

Methods: In our study, we used techniques such as high-throughput Sequencing, tissue transmission electron microscopy, cell scanning electron microscopy, and multi-label immunofluorescence staining co-localization.

Results: We found that as inflammation progresses, NETs secreted by neutrophils can induce macrophage Pyroptosis by promoting the activation of AIM2. The Pyroptosis macrophages can promote abnormal differentiation of tendon stem cells, thereby promoting the formation of tHO. To find an effective solution, we creatively combined different chiral lysines with Bacterial cellulose and successfully prevented the formation of tHO.

Conclusion: Our research not only reveals from a new perspective that the IL-1β-NETs-AIM2 axis participates in the formation of tHO by orchestrating crosstalk between neutrophils and macrophages, but also provides a novel approach for the future clinical treatment of tHO.

Keywords

AIM2; Chirality; IL-1β; Lysine; NETs; Trauma-induced heterotopic ossification.

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