Low dose ionizing radiation promotes motor functional restoration in a mouse model of traumatic brain injury

Traumatic brain injury (TBI) is a form of mechanical insult to the brain leading to irreversible motor functional impairments in TBI patients. TBI remains as a leading cause of disability and morbidity in the globe. The injured neurons in the central nervous system (CNS) have limited regenerative capacity to regrow their damaged axons across the lesion for target reinnervation following injuries. The presence of extrinsic growth inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) at the lesion further impede axon regeneration after injuries. Currently, there is no effective therapy aimed to improve functional restoration in TBI patients. In recent years, emerging evidence suggested that low dose of ionizing radiation (LDIR) exhibits a wide range of beneficial effects to irradiated individuals. For instance, single exposure to LDIR exerts neuroprotective effects in various neurological disorders including Parkinson’s disease, retinitis pigmentosa, glaucoma and spinal cord injury. This prompted us to investigate the potential hormetic effects of LDIR on promoting CNS repair after TBI. We performed a stab wound injury in motor cortex of postnatal and adult C57BL/6 mice, respectively. The mice were then received a single whole-body exposure of LDIR immediately after injury. In both postnatal and adult mice, LDIR markedly accelerated wound closure with a marked reduction in apoptotic neurons 7 days after cortical stab wound injury. More importantly, we observed a marked improvement in motor functions from irradiated mice as assessed by pole climbing test, grip strength test and beam walking test after injury. Further histological analysis revealed that LDIR markedly increased microglial density, associated with a marked reduction in CSPG deposition at the lesion 6 hours and 7 days after injury. We confirmed that the increased microglial density at the lesion was due to the promoted microglial migration towards the lesion, but not due to increase in microglial proliferation. Cytokine profiling and qPCR analysis on irradiated microglia suggested that LDIR promoted microglial M1-to-M2 switch, with increased expression of genes involved in neuroprotection, CSPG degradation and phagocytosis. Taken together, our study demonstrated for the first time that LDIR promoted CNS repair and functional restoration via immunomodulation of microglia after TBI, shedding new light in developing alternative therapeutic approaches for TBI patients to improve functional outcomes after injuries.