title: P2Y6 Receptor-Mediated Microglial Phagocytosis in Radiation-Induced Brain Injury.
abstract: Microglia are the resident immune cells and the professional phagocytic cells of the CNS, showing a multitude of cellular responses after activation. However, how microglial phagocytosis changes and whether it is involved in radiation-induced brain injury remain unknown. In the current study, we found that microglia were activated and microglial phagocytosis was increased by radiation exposure both in cultured microglia in vitro and in mice in vivo. Radiation increased the protein expression of the purinergic receptor P2Y6 receptor (P2Y6R) located on microglia. The selective P2Y6 receptor antagonist MRS2578 suppressed microglial phagocytosis after radiation exposure. Inhibition of microglial phagocytosis increased inhibitory factor Nogo-A and exacerbated radiation-induced neuronal apoptosis and demyelination. We also found that the levels of protein expression for phosphorylated Ras-related C3 botulinum toxin substrate 1 (Rac1) and myosin light chain kinase (MLCK) were elevated, indicating that radiation exposure activated Rac1 and MLCK. The Rac1 inhibitor NSC23766 suppressed expression of MLCK, indicating that the Rac1-MLCK pathway was involved in microglial phagocytosis. Taken together, these findings suggest that the P2Y6 receptor plays a critical role in mediating microglial phagocytosis in radiation-induced brain injury, which might be a potential strategy for therapeutic intervention to alleviate radiation-induced brain injury.
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Number 107, Yan Jiang Xi Road, Guangzhou, Guangdong Province, 510120, China.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen University, Guangzhou, 510120, China.
authors.forename: Yongteng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, Cancer Center of Sun Yat-Sen University, Guangzhou, 510120, China.
authors.forename: Weihan
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Number 107, Yan Jiang Xi Road, Guangzhou, Guangdong Province, 510120, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Number 107, Yan Jiang Xi Road, Guangzhou, Guangdong Province, 510120, China.
authors.forename: Zichen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Number 107, Yan Jiang Xi Road, Guangzhou, Guangdong Province, 510120, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Number 107, Yan Jiang Xi Road, Guangzhou, Guangdong Province, 510120, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Number 107, Yan Jiang Xi Road, Guangzhou, Guangdong Province, 510120, China. yameitang@hotmail.com.|Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-Sen University, Guangzhou, 510120, China. yameitang@hotmail.com.
authors.forename: Yamei
authors.initials: Y
authors.lastname: Tang
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000209:etiology* / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010455:Peptides / Q000378:metabolism; D010587:Phagocytosis; D011832:Radiation Injuries / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D010455:Peptides; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; C065738:MLCK peptide; D020830:rac1 GTP-Binding Protein
keywords: MLCK; Microglial phagocytosis; Myelin; Neuronal apoptosis; P2Y6 receptor; Rac1; Radiation-induced brain injury