Sleep-restriction Inhibits Neurogenesis Through Decreasing the Infiltration of CD169+ Macrophages to Ischemic Brain After Stroke

Abstract

Chronic sleep-restriction (SR) is shown to be correlated with neurodevelopmental disorders. However, the effects of SR during stroke recovery on neurorepair remain unclear. In this study, mice were subjected to 60 min of cerebral ischemia followed by reperfusion. The SR protocol was accomplished by depriving mice of sleep for 20 h/day for 14 days starting at 14 days post-ischemia. We found that SR increased CD169+ macrophages infiltration into the ischemic brain parenchyma and inhibited neurogenesis and functional recovery. SR decreased CD169+ macrophages infiltration into the choroid plexus (CP) and cerebrospinal fluid (CSF), accompanied by increased expression of Chemokine C-X3-C-Motif Ligand 1 (CX3CL1) and intercellular adhesion molecule (ICAM-1) via IFN-γ/IFN-γR signaling in the CP. When splenic CD169+ macrophages sorted from Kaede transgenic mice were administered into CSF of C57BL/6 mice, they homed to the ischemic brain parenchyma. Moreover, blockade of IFN-γ/IFN-γR signaling, CX3CL1 or ICAM-1 decreased CD169+ macrophages infiltration into the CP, CSF and ischemic brain parenchyma, as well as decreasing neurogenesis and functional recovery after SR. The promoting roles of infiltrated CD169+ macrophages in post-stroke neurogenesis were due to increasing regulatory T cells (Tregs) in the ischemic brain parenchyma. Furthermore, dexmedetomidine treatment during SR increased CD169+ macrophages infiltration into the CP, CSF and ischemic brain parenchyma, and promoted neurogenesis and functional recovery. Taken together, our results showed that SR during stroke recovery decreased Tregs in the ischemic brain parenchyma by decreasing CD169+ macrophages infiltration to the ischemic brain parenchyma across the CP, which inhibited neurogenesis and functional recovery.