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Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling
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 de...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923664/ https://www.ncbi.nlm.nih.gov/pubmed/35244027 http://dx.doi.org/10.7554/eLife.75753 |
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author | Sun, Kai Wang, Chun Xiao, Jianqiu Brodt, Michael D Yuan, Luorongxin Yang, Tong Alippe, Yael Hu, Huimin Hao, Dingjun Abu-Amer, Yousef Silva, Matthew J Shen, Jie Mbalaviele, Gabriel |
author_facet | Sun, Kai Wang, Chun Xiao, Jianqiu Brodt, Michael D Yuan, Luorongxin Yang, Tong Alippe, Yael Hu, Huimin Hao, Dingjun Abu-Amer, Yousef Silva, Matthew J Shen, Jie Mbalaviele, Gabriel |
author_sort | Sun, Kai |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8923664 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-89236642022-03-16 Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling Sun, Kai Wang, Chun Xiao, Jianqiu Brodt, Michael D Yuan, Luorongxin Yang, Tong Alippe, Yael Hu, Huimin Hao, Dingjun Abu-Amer, Yousef Silva, Matthew J Shen, Jie Mbalaviele, Gabriel eLife Immunology and Inflammation 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. eLife Sciences Publications, Ltd 2022-03-04 /pmc/articles/PMC8923664/ /pubmed/35244027 http://dx.doi.org/10.7554/eLife.75753 Text en © 2022, Sun et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Immunology and Inflammation Sun, Kai Wang, Chun Xiao, Jianqiu Brodt, Michael D Yuan, Luorongxin Yang, Tong Alippe, Yael Hu, Huimin Hao, Dingjun Abu-Amer, Yousef Silva, Matthew J Shen, Jie Mbalaviele, Gabriel Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling |
title | Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling |
title_full | Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling |
title_fullStr | Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling |
title_full_unstemmed | Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling |
title_short | Fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling |
title_sort | fracture healing is delayed in the absence of gasdermin-interleukin-1 signaling |
topic | Immunology and Inflammation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8923664/ https://www.ncbi.nlm.nih.gov/pubmed/35244027 http://dx.doi.org/10.7554/eLife.75753 |
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