LC3 Accelerated Brain-Lung Axis Abscopal Effects after Fractionated Whole-Brain Radiation by Promoting Motoneurons to Secrete Periostin.

ABSTRACT

The effect of autophagy on the radiation-induced bystander effect (RIBE) in vivo is unclear. Here, the whole brains of microtubule-associated protein 1A/1B-light chain 3 (LC3) and C57BL/6 (B6) mice were irradiated once (10 Gy)(IR1), given 3 fractions in three weeks (IR3), or 6 fractions in six weeks (IR6). The median survival of LC3 mice was 56.5 days, and that of B6 mice was 65 days after IR6. LC3 mice showed more congestion and fibrosis in the lung after the IR3 and IR6 irradiation protocols than B6 mice. Quantitative proteomics of serum samples and lung RNA sequencing of the LC3 group showed that the common most clustered pathway of the IR3 group was the elastic fiber formation pathway, which contained Periostin (POSTN). POSTN in the motoneurons increased with increasing number of radiation fractions in LC3 mice. A 1 µg/g POSTN neutralizing antibody reduced the lung fibrosis of LC3 mice exposed to IR3 by one-third, and significantly prolonged the survival time of LC3 mice exposed to IR6. LDN-214117 and LRRK2-in-1 were the best two of sixteen transforming growth factor-beta1 (TGF-ß) receptor and autophagy mediators to decrease Postn mRNA. These data led us to conclude that LC3 accelerated motoneuron secretion of POSTN and aggravated the RIBE in the lung after brain irradiation.