NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation.
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.
Jung-Hyun
JH
Kim
Rajesh K
RK
Thimmulappa
Vineet
V
Kumar
Wanchang
W
Cui
Sarvesh
S
Kumar
Ponvijay
P
Kombairaju
Hao
H
Zhang
Joseph
J
Margolick
William
W
Matsui
Thomas
T
Macvittie
Sanjay V
SV
Malhotra
Shyam
S
Biswal
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D019070:Cell Lineage; D047188:Chalcones / Q000737:chemistry; D003598:Cytoskeletal Proteins / Q000235:genetics; D006098:Granulocytes / Q000528:radiation effects; D006410:Hematopoiesis / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000528:radiation effects*; D000072019:Kelch-Like ECH-Associated Protein 1; D008214:Lymphocytes / Q000528:radiation effects; D008533:Megakaryocytes / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000528:radiation effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D017382:Reactive Oxygen Species; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction
C561055:2-trifluoromethyl-2'-methoxychalone; D048868:Adaptor Proteins, Signal Transducing; D047188:Chalcones; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D051880:Receptors, Notch