Radiation causes tissue damage by dysregulating inflammasome-gasdermin D signaling in both host and transplanted cells.
Radiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages ti...
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2020-08-01
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Online Access: | https://doi.org/10.1371/journal.pbio.3000807 |
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doaj-dfcc01b5a9e84be9b30dca2343479fa02021-07-02T21:43:39ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852020-08-01188e300080710.1371/journal.pbio.3000807Radiation causes tissue damage by dysregulating inflammasome-gasdermin D signaling in both host and transplanted cells.Jianqiu XiaoChun WangJuo-Chin YaoYael AlippeTong YangDustin KressKai SunKourtney L KosteckiJoseph B MonahanDeborah J VeisYousef Abu-AmerDaniel C LinkGabriel MbalavieleRadiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages tissues, thereby unleashing signals that indiscriminately activate the inflammasome pathways in host and transplanted cells. We find that a clinically relevant high dose of radiation causes severe damage to bones and the spleen through mechanisms involving the NLRP3 and AIM2 inflammasomes but not the NLRC4 inflammasome. Downstream, we demonstrate that gasdermin D (GSDMD), the common effector of the inflammasomes, is also activated by radiation. Remarkably, protection against the injury induced by deadly ionizing radiation occurs only when NLRP3, AIM2, or GSDMD is lost simultaneously in both the donor and host cell compartments. Thus, this study reveals a continuum of the actions of lethal radiation relayed by the inflammasome-GSDMD axis, initially affecting recipient cells and ultimately harming transplanted cells as they grow in the severely injured and toxic environment. This study also suggests that therapeutic targeting of inflammasome-GSDMD signaling has the potential to prevent the collateral effects of intense radiation regimens.https://doi.org/10.1371/journal.pbio.3000807 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jianqiu Xiao Chun Wang Juo-Chin Yao Yael Alippe Tong Yang Dustin Kress Kai Sun Kourtney L Kostecki Joseph B Monahan Deborah J Veis Yousef Abu-Amer Daniel C Link Gabriel Mbalaviele |
spellingShingle |
Jianqiu Xiao Chun Wang Juo-Chin Yao Yael Alippe Tong Yang Dustin Kress Kai Sun Kourtney L Kostecki Joseph B Monahan Deborah J Veis Yousef Abu-Amer Daniel C Link Gabriel Mbalaviele Radiation causes tissue damage by dysregulating inflammasome-gasdermin D signaling in both host and transplanted cells. PLoS Biology |
author_facet |
Jianqiu Xiao Chun Wang Juo-Chin Yao Yael Alippe Tong Yang Dustin Kress Kai Sun Kourtney L Kostecki Joseph B Monahan Deborah J Veis Yousef Abu-Amer Daniel C Link Gabriel Mbalaviele |
author_sort |
Jianqiu Xiao |
title |
Radiation causes tissue damage by dysregulating inflammasome-gasdermin D signaling in both host and transplanted cells. |
title_short |
Radiation causes tissue damage by dysregulating inflammasome-gasdermin D signaling in both host and transplanted cells. |
title_full |
Radiation causes tissue damage by dysregulating inflammasome-gasdermin D signaling in both host and transplanted cells. |
title_fullStr |
Radiation causes tissue damage by dysregulating inflammasome-gasdermin D signaling in both host and transplanted cells. |
title_full_unstemmed |
Radiation causes tissue damage by dysregulating inflammasome-gasdermin D signaling in both host and transplanted cells. |
title_sort |
radiation causes tissue damage by dysregulating inflammasome-gasdermin d signaling in both host and transplanted cells. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Biology |
issn |
1544-9173 1545-7885 |
publishDate |
2020-08-01 |
description |
Radiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages tissues, thereby unleashing signals that indiscriminately activate the inflammasome pathways in host and transplanted cells. We find that a clinically relevant high dose of radiation causes severe damage to bones and the spleen through mechanisms involving the NLRP3 and AIM2 inflammasomes but not the NLRC4 inflammasome. Downstream, we demonstrate that gasdermin D (GSDMD), the common effector of the inflammasomes, is also activated by radiation. Remarkably, protection against the injury induced by deadly ionizing radiation occurs only when NLRP3, AIM2, or GSDMD is lost simultaneously in both the donor and host cell compartments. Thus, this study reveals a continuum of the actions of lethal radiation relayed by the inflammasome-GSDMD axis, initially affecting recipient cells and ultimately harming transplanted cells as they grow in the severely injured and toxic environment. This study also suggests that therapeutic targeting of inflammasome-GSDMD signaling has the potential to prevent the collateral effects of intense radiation regimens. |
url |
https://doi.org/10.1371/journal.pbio.3000807 |
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