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In the clinical setting, repeated exposures (10–30) to low-doses of ionizing radiation (≤ 200 cGy), as seen in radiotherapy for cancer, causes fatigue. Almost nothing is known, however, about the fatigue inducing effects of a single exposure to environmental low-dose ionizing radiation that might occur during high-altitude commercial air flight, a nuclear reactor accident or a solar particle event (SPE). To investigate the short-term impact of low-dose ionizing radiation on mouse biobehaviors and neuroimmunity, male CD-1 mice were whole body irradiated with 50 cGy or 200 cGy of gamma or proton radiation. Gamma radiation was found to reduce spontaneous locomotor activity by 35% and 36%, respectively, 6 h post irradiation. In contrast, the motivated behavior of social exploration was un-impacted by gamma radiation. Examination of pro-inflammatory cytokine gene transcripts in the brain demonstrated that gamma radiation increased hippocampal TNF-α expression as early as 4 h post-irradiation. This was coupled to subsequent increases in IL-1RA (8 h and 12 h post irradiation) in the cortex and hippocampus and reductions in activity-regulated cytoskeleton-associated protein (Arc) (24 h post irradiation) in the cortex. Finally, restraint stress was a significant modulator of the neuroimmune response to radiation blocking the ability of 200 cGy gamma radiation from impairing locomotor activity and altering the brain-based inflammatory response to irradiation. Taken together, these findings indicate that low-dose ionizing radiation rapidly activates the neuroimmune system potentially causing early onset fatigue-like symptoms in mice.

IL-1R2 is a critical regulator of IL-1 bioaction but its role in acute hypoxia is not clear. Here we examine its expression during acute hypoxia. Male mice were exposed to a 6% O2 environment for 2 h. Gene transcripts for 28 inflammation-associated bioactives were examined in brain, liver, spleen, fat, and lung, and the transcript with the greatest fold elevation in all tissues was IL-1R2. In order to determine the likely cell of origin, we isolated macrophages and endothelial cells from lung because these two cell types were common to all of the aforementioned tissues. Lung macrophages from hypoxic mice expressed 104- and 163-fold more IL-1R2 than lung endothelial cells or lung tissue where the macrophages and endothelial cells had been removed. Importantly, hypoxic lung macrophages expressed four-fold more IL-1R2 than normoxic lung macrophages. Lung macrophages exposed to hypoxia ex-vivo did not up-regulate IL-1R2. Lung macrophages transferred to the peritoneum demonstrated a 225-fold increase in IL-1R2. These findings indicate the hypoxia-dependent up-regulation of IL-1R2 occurs in macrophages and is reliant on signals derived from the in vivo microenvironment.