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.
Highlights
Primary tumors affecting the head, neck, and brain as well as brain metastases occurring in 20–40 % of patients with cancer account for significant morbidity and mortality [1, 2]
We showed that microglial phagocytosis increased after radiation, efficiently removing the inhibitory factor neurite outgrowth inhibitor (Nogo)-A from the myelin debris and engulfing apoptotic neurons
This increase in microglial phagocytosis was paralleled by an increase in the expression of the P2Y6 receptor protein localized to microglia
Summary
Primary tumors affecting the head, neck, and brain as well as brain metastases occurring in 20–40 % of patients with cancer account for significant morbidity and mortality [1, 2]. Radiotherapy, helpful in the management of central nervous system (CNS) and head and neck tumors, can cause devastating injury to normal CNS tissues [5, 6]. The exact pathogenic mechanisms of radiation-induced brain injury remain largely unknown, studies have demonstrated that microglia may play a pivotal role by releasing proinflammatory factors that induce an inflammatory response when activated by radiation [7, 8]. In addition to this inflammatory response aspect, microglia are professional phagocytes in the CNS, maintaining homeostasis of the nervous system [9]. The efficient clearance of apoptotic cells may prevent the accumulation of necrotic cells and the subsequent release of
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