2. Academic Validation
  3. STING contributes to trauma-induced heterotopic ossification through NLRP3-dependent macrophage pyroptosis

STING contributes to trauma-induced heterotopic ossification through NLRP3-dependent macrophage pyroptosis

  • Clin Immunol. 2023 Mar 22;250:109300. doi: 10.1016/j.clim.2023.109300.
Ziyang Sun 1,  Hang Liu 1,  Yuehao Hu 2,  Gang Luo 1,  Zhengqiang Yuan 1,  Bing Tu 1,  Hongjiang Ruan 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 201306, PR China.
  • 2 Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, 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 201306, PR China. Electronic address: ruanhongjiang@126.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 201306, 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 201306, PR China. Electronic address: cyfan@sjtu.edu.cn.
PMID: 36963448 DOI: 10.1016/j.clim.2023.109300
Abstract

Trauma-induced heterotopic ossification (HO) is featured by aberrant bone formation at extra-skeletal site. STING is a master adaptor protein linking cellular damage to immune responses, while its role in HO remains elusive. A murine burn/tenotomy model was used to mimic trauma-induced HO in vivo. We demonstrated elevated STING expression in macrophages in inflammatory stage after burn/tenotomy, and STING inhibition significantly alleviated HO formation. Activated NLRP3-dependent macrophage Pyroptosis was also found in inflammatory stage after burn/tenotomy. Either STING or NLRP3 suppression reduced mature HO by weakening macrophage pyroptotic inflammation, while protective effects of STING were abolished by NLRP3 overexpression. Further, in vitro, we also found a prominent STING level in pyroptotic BMDMs. STING suppression relieved macrophage pyroptotic inflammation, while abolished by NLRP3 overexpression. Our results reveal that STING poses regulatory effects on trauma-induced HO formation, via modulating NLRP3-dependent macrophage Pyroptosis. Targeting STING-NLRP3 axis represents an attractive approach for trauma-induced HO prevention.

Keywords

Heterotopic ossification; Macrophages; Nucleotide-binding and oligomerization domain-like receptor 3 (NLRP3); Pyroptosis; Stimulator of interferon genes (STING).

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