Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling
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Evaluation Summary:
The paper by Sun et al. addresses the role of gasdermins GSDMD and GSDME in fracture healing and inflammation after injury. The study is very significant for the understanding the role of GSDMD and GSDME in bone homoeostasis and in particular fracture healing. The reported data are very strong and in support of the proposed/studied hypothesis.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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- Evaluated articles (eLife)
- Immunology and Inflammation (eLife)
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.
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Evaluation Summary:
The paper by Sun et al. addresses the role of gasdermins GSDMD and GSDME in fracture healing and inflammation after injury. The study is very significant for the understanding the role of GSDMD and GSDME in bone homoeostasis and in particular fracture healing. The reported data are very strong and in support of the proposed/studied hypothesis.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Public Review:
In the manuscript by Sun et al the authors examine the roles played by the gasdermin-interleukin axis in the fracture healing process. Gasdermins (GSDMs) form plasma membrane pores and thus enable secretion of interleukins 1β and 18. These proinflammatory interleukins then initiate fracture healing. The authors utilize a variety of models to demonstrate the importance of interleukin 1β in this process including: (1) GSDM knockout mice; (2) tibia fracture model and (3) interleukin 1 knockout mice. The use of various in vivo and in vitro testing is a strength of the manuscript convincingly demonstrating a role for interleukin 1β in fracture healing. A weakness of the manuscript is that a potential role for interleukin 18 is underdeveloped and not as convincing as that for interleukin 1β. The authors themselves point this …
Public Review:
In the manuscript by Sun et al the authors examine the roles played by the gasdermin-interleukin axis in the fracture healing process. Gasdermins (GSDMs) form plasma membrane pores and thus enable secretion of interleukins 1β and 18. These proinflammatory interleukins then initiate fracture healing. The authors utilize a variety of models to demonstrate the importance of interleukin 1β in this process including: (1) GSDM knockout mice; (2) tibia fracture model and (3) interleukin 1 knockout mice. The use of various in vivo and in vitro testing is a strength of the manuscript convincingly demonstrating a role for interleukin 1β in fracture healing. A weakness of the manuscript is that a potential role for interleukin 18 is underdeveloped and not as convincing as that for interleukin 1β. The authors themselves point this out in the Discussion section. The authors raise the possibility that their findings are translationally relevant with the development of GSDM inhibitors for clinical use.
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