TY - JOUR
T1 - NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation
AU - Kim, Jung Hyun
AU - Thimmulappa, Rajesh K.
AU - Kumar, Vineet
AU - Cui, Wanchang
AU - Kumar, Sarvesh
AU - Kombairaju, Ponvijay
AU - Zhang, Hao
AU - Margolick, Joseph
AU - Matsui, William
AU - Macvittie, Thomas
AU - Malhotra, Sanjay V.
AU - Biswal, Shyam
PY - 2014/2/3
Y1 - 2014/2/3
N2 - A nuclear disaster may result in exposure to potentially lethal doses of ionizing radiation (IR). Hematopoietic acute radiation syndrome (H-ARS) is characterized by severe myelosuppression, which increases the risk of infection, bleeding, and mortality. Here, we determined that activation of nuclear factor erythroid-2.related factor 2 (NRF2) signaling enhances hematopoietic stem progenitor cell (HSPC) function and mitigates IR-induced myelosuppression and mortality. Augmenting NRF2 signaling in mice, either by genetic deletion of the NRF2 inhibitor Keap1 or by pharmacological NRF2 activation with 2-trifluoromethyl-2′-methoxychalone (TMC), enhanced hematopoietic reconstitution following bone marrow transplantation (BMT). Strikingly, even 24 hours after lethal IR exposure, oral administration of TMC mitigated myelosuppression and mortality in mice. Furthermore, TMC administration to irradiated transgenic Notch reporter mice revealed activation of Notch signaling in HSPCs and enhanced HSPC expansion by increasing Jagged1 expression in BM stromal cells. Administration of a Notch inhibitor ablated the effects of TMC on hematopoietic reconstitution. Taken together, we identified a mechanism by which NRF2-mediated Notch signaling improves HSPC function and myelosuppression following IR exposure. Our data indicate that targeting this pathway may provide a countermeasure against the damaging effects of IR exposure.
AB - A nuclear disaster may result in exposure to potentially lethal doses of ionizing radiation (IR). Hematopoietic acute radiation syndrome (H-ARS) is characterized by severe myelosuppression, which increases the risk of infection, bleeding, and mortality. Here, we determined that activation of nuclear factor erythroid-2.related factor 2 (NRF2) signaling enhances hematopoietic stem progenitor cell (HSPC) function and mitigates IR-induced myelosuppression and mortality. Augmenting NRF2 signaling in mice, either by genetic deletion of the NRF2 inhibitor Keap1 or by pharmacological NRF2 activation with 2-trifluoromethyl-2′-methoxychalone (TMC), enhanced hematopoietic reconstitution following bone marrow transplantation (BMT). Strikingly, even 24 hours after lethal IR exposure, oral administration of TMC mitigated myelosuppression and mortality in mice. Furthermore, TMC administration to irradiated transgenic Notch reporter mice revealed activation of Notch signaling in HSPCs and enhanced HSPC expansion by increasing Jagged1 expression in BM stromal cells. Administration of a Notch inhibitor ablated the effects of TMC on hematopoietic reconstitution. Taken together, we identified a mechanism by which NRF2-mediated Notch signaling improves HSPC function and myelosuppression following IR exposure. Our data indicate that targeting this pathway may provide a countermeasure against the damaging effects of IR exposure.
UR - http://www.scopus.com/inward/record.url?scp=84893836947&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84893836947&partnerID=8YFLogxK
U2 - 10.1172/JCI70812
DO - 10.1172/JCI70812
M3 - Article
C2 - 24463449
AN - SCOPUS:84893836947
SN - 0021-9738
VL - 124
SP - 730
EP - 741
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -