Fracture healing is delayed in the absence of gasdermin - interleukin-1 signaling
- Washington University School of Medicine, United States
- First Affiliated Hospital of Xi'an Jiaotong University, China
Abstract
Amino-terminal fragments from proteolytically cleaved gasdermins (GSDMs) form plasma membrane pores that enable the secretion of interleukin-1β (IL-1β) and IL-18. Excessive GSDM-mediated pore formation can compromise the integrity of the plasma membrane thereby causing the lytic inflammatory cell death, pyroptosis. We found that GSDMD and GSDME were the only GSDMs that were readily expressed in bone microenvironment. Therefore, we tested the hypothesis that GSDMD and GSDME are implicated in fracture healing owing to their role in the obligatory inflammatory response following injury. We found that bone callus volume and biomechanical properties of injured bones were significantly reduced in mice lacking either GSDM compared with wild-type (WT) mice, indicating that fracture healing was compromised in mutant mice. However, compound loss of GSDMD and GSDME did not exacerbate the outcomes, suggesting shared actions of both GSDMs in fracture healing. Mechanistically, bone injury induced IL-1β and IL-18 secretion in vivo, a response that was mimicked in vitro by bone debris and ATP, which function as inflammatory danger signals. Importantly, the secretion of these cytokines was attenuated in conditions of GSDMD deficiency. Finally, deletion of IL-1 receptor reproduced the phenotype of Gsdmd or Gsdme deficient mice, implying that inflammatory responses induced by the GSDM-IL-1 axis promote bone healing after fracture.
Data availability
All data generated or analy5ed during this study are included in the manuscript and supporting file; Source Data files have been provided for all figures.
Article and author information
Author details
Gabriel Mbalaviele
Funding
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR076758)
- Gabriel Mbalaviele
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR074992)
- Matthew J Silva
National Institute of Allergy and Infectious Diseases (AI161022)
- Gabriel Mbalaviele
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR075860)
- Jie Shen
National Institute of Allergy and Infectious Diseases (AR077616)
- Jie Shen
National Institute of Allergy and Infectious Diseases (AR077226)
- Jie Shen
National Institute of Allergy and Infectious Diseases (AR049192)
- Yousef Abu-Amer
National Institute of Allergy and Infectious Diseases (AR074992)
- Yousef Abu-Amer
National Institute of Allergy and Infectious Diseases (AR072623)
- Yousef Abu-Amer
Shriners Hospitals for Children (85160)
- Yousef Abu-Amer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were on the C57BL6J background, and genotyping was performed by PCR. All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Washington University School of Medicine in St. Louis. All experiments were performed in accordance with the relevant guidelines and regulations described in the IACUC- approved protocol 19-0971.
Copyright
© 2022, Sun et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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