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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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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