Mild, systemic heat treatment enhances neutrophil recovery following total body irradiation
Capitano, Maegan L.
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Patients exposed to total body irradiation often experience treatment-induced neutropenia which increases the risk of serious infection. Previous research from our laboratory and others demonstrated that raising core body temperature into the fever-range (39.5°C) affects neutrophil numbers in the peripheral blood or in tissues in mice with bacterial infections or when given LPS. Recognizing that radiation exposure triggers similar inflammatory pathways as infection, we hypothesize that heat treatment given after total body irradiation (TBI) may alter neutrophil numbers in the peripheral blood in a mouse model of radiation-induced neutropenia tapping into homeopathic mechanisms associated with the regulation of neutrophil numbers following a stress event. We also explored potential mechanisms by which the cytokine milieu responsible for homeostatic regulation of neutrophils could be impacted by elevated body temperature. For our experimental model, mice were given TBI (3 or 6Gy) followed 2 hours later by a mild heating (39.5°C). In mice that received heat treatment following TBI, a significant increase in peripheral blood neutrophil numbers was observed compared to mice that received radiation alone or heating alone. In addition, systemic G-CSF concentrations were increased in irradiated/heated mice and neutralization of G-CSF resulted in the inability of heat to enhance neutrophil recovery. IL-17 concentrations were also increased in the intestine in animals that received heat treatment following TBI. Neutrophil recovery assays in IL17ra -/- mice revealed that IL-17 signaling was necessary for the thermal enhancement in neutrophil recovery. Flow analysis of the bone marrow from wild type mice revealed an increase in progenitor cell numbers in mice treated with radiation then mild heating. This increase in progenitor numbers in radiated/heated mice was associated with an increase in overall number of CFUs when compared to radiation alone. There was also an observable difference in the timing and magnitude of the thermal response when comparing results in our neutrophil recovery, cytokine, and CFU assays indicating that the thermal effect was dependent on the radiation dose received. These data reveal a previously unexplored role of body temperature in regulation of hematopoiesis and marrow output following radiation exposure and may help in the development of novel, clinically applicable strategies to ameliorate the effects of TBI.