TY - JOUR
T1 - Radiation causes tissue damage by dysregulating inflammasome–gasdermin D signaling in both host and transplanted cells
AU - Xiao, Jianqiu
AU - Wang, Chun
AU - Yao, Juo Chin
AU - Alippe, Yael
AU - Yang, Tong
AU - Kress, Dustin
AU - Sun, Kai
AU - Kostecki, Kourtney L.
AU - Monahan, Joseph B.
AU - Veis, Deborah J.
AU - AbuAmer, Yousef
AU - Link, Daniel C.
AU - Mbalaviele, Gabriel
N1 - Publisher Copyright:
© 2020 Xiao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/8/6
Y1 - 2020/8/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85089712690&partnerID=8YFLogxK
U2 - 10.1371/JOURNAL.PBIO.3000807
DO - 10.1371/JOURNAL.PBIO.3000807
M3 - Article
C2 - 32760056
AN - SCOPUS:85089712690
SN - 1544-9173
VL - 18
JO - PLoS biology
JF - PLoS biology
IS - 8
M1 - e3000807
ER -