TY - JOUR
T1 - Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling
AU - Sun, Kai
AU - Wang, Chun
AU - Xiao, Jianqiu
AU - Brodt, Michael D.
AU - Yuan, Luorongxin
AU - Yang, Tong
AU - Alippe, Yael
AU - Hu, Huimin
AU - Hao, Dingjun
AU - Abu-Amer, Yousef
AU - Silva, Matthew J.
AU - Shen, Jie
AU - Mbalaviele, Gabriel
N1 - Funding Information:
This work was supported by NIH/NIAMS AR076758 and AI161022 grants to GM. JS was supported by NIH grants AR075860, AR077616, and AR077226; YA-A by NIH grants AR049192, AR074992, AR072623, and by grant #85160 from the Shriners Hospital for Children; MJS, by NIH grants AR074992.
Publisher Copyright:
© Sun et al.
PY - 2022/3
Y1 - 2022/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85126830704&partnerID=8YFLogxK
U2 - 10.7554/eLife.75753
DO - 10.7554/eLife.75753
M3 - Article
C2 - 35244027
AN - SCOPUS:85126830704
SN - 2050-084X
VL - 11
JO - eLife
JF - eLife
M1 - e75753
ER -