Radiation exposure induced blood-brain barrier injury via mitochondria-mediated sterile inflammation

Radiation-induced brain injury (RIBI) is caused by exposure to high doses of ionizing radiation and characterized by severe cognitive dysfunction and brain necrosis. The widespread application of radiotherapy and rapid development of deep space exploration have substantially increased the risk of RIBI. However, the pathogenesis of RIBI is not fully understood, and no effective intervention is available. This work described a blood-brain barrier (BBB) microphysiological system (MPS), that allowed to explore the responses of BBB and distinct brain cells to radiation exposure. This BBB MPS can recapitulate the interface structure and function of BBB in brain microenvironment, including brain endothelial cells, astrocytes, pericytes and microglia co-cultured under flow condition. Following acute exposure to radiation of X-ray or {gamma}-ray, characteristic RIBI-associated pathological responses were observed, including BBB compromise, DNA breaks, inhibited cell proliferation, cell hypertrophy and pro-inflammatory cytokine release. Among the distinctive types of cells, brain endothelial cells showed the highest radiosensitivity as compared to other cells in the MPS. Intriguingly, X-ray and {gamma}-ray radiation consistently induced prominent sterile inflammation responses, especially type I interferon response, in the BBB MPS. These responses were mediated by radiation-induced mitochondrial DNA release and subsequent activation of cGAS-STING signaling pathway. Furthermore, we found abrocitinib (JAK1 inhibitor) and idebenone (mitochondrial protectant) can attenuate radiation-induced inflammation and ameliorate BBB injury. These findings revealed the involvement of mitochondria-mediated inflammation in RIBI pathogenesis, identifying mitochondria as a potential target for new radioprotective measures.