IL-1β Impedes Oligodendrocyte Progenitor Cell Migration After Chronic Cerebral Ischemia

Objective:Subcortical ischemic vascular dementia (SIVD) induced by chronic hypoperfusion is a common subtype of vascular dementia, with characteristics of white matter damage and cognitive behavior impairment, yet the detailed pathogenic mechanism is still unclear. Our previous and others work imply that glial activation participates in the development of SIVD. IL-1β is one of the major proinflammatory cytokines secreted by glia, however, its role in SIVD is not appreciated.Methods:IL-1 receptor knockout (IL-1R KO) mice or wide type mice (C57BL/6 strain) were subjected to right unilateral common carotid arteries occlusion (rUCCAO), an experimental mouse model of SIVD, and treated with IL-1 receptor antagonist (IL-1Ra). Immunohistochemistry, electron microscopy, object recognition test and morris water maze test were performed after rUCCAO.Results:We found that IL-1β, mainly derives from astrocyte, elevated from 1d to 7d and returned to baseline at 14d in corpus callosum after rUCCAO. Administration of IL-1 Ra, from 1d to 7d (1 μg, i.c.v.), rescued the downregulation of MBP caused by hypoperfusion on 34d. Electron microscopy showed that IL-1 Ra treatment increased the number of myelinated axons compared with saline treated group 34d after rUCCAO, which largely refers to axons with thin myelins. In IL-1R KO mice, there is no difference between rUCCAO group and sham group both in MBP expression and myelin numbers, while the percentage of axons with thin myelin increased after hypoperfusion. We also showed that IL-1 Ra reversed the decrease of NG2+ oligodendrocyte progenitor cells (OPCs) number in corpus callosum at 8d after hypoperfusion, however IL-1R KO mice did not display obvious loss of OPCs after hypoperfusion. Further study indicated that there is no difference in the number of oligodendrocytes undergoing proliferation in subventricular zone (SVZ) between rUCCAO group and IL-1 Ra treated group, examined by PCNA or Ki67 immunostaining, whereas in corpus callosum we did not observe any proliferating cells. Besides, by using Brdu (5-bromo,2deoxyuridine) labeling we confirmed that IL-1β did not affect the proliferation of OPCs in SVZ. However, we found that IL-1 Ra and IL-1R KO increased the number of Brdu+ NG2+ cells in corpus callosum after hypoperfusion, which suggests that IL-1β inhibits OPCs recruitment from SVZ to corpus callosum to inhibit remyelination. To further verify that, the proliferating newborn cells in SVZ are traced by retrovirus injection, and we found that IL-1Ra treatment elevated newborn cell number in corpus callosum, which can be reversed by co-treatment with IL-1β. In addition, IL-1R KO mice also exhibited the upregulation of newborn cell number in corpus callosum after rUCCAO. Moreover, IL-1 Ra administration significantly rescued the decrease of the discrimination index in object cognition test, the increase of escape latency during the acquisition trials and the reduction of time spent in the target quadrant in Morris water test at 28d after rUCCAO, while IL-1R KO animals did not exhibit any cognitive impairment after hypoperfusion, which suggests that IL-1β impaired learning and memory ability caused by hypoperfusion.Conclusion:The upregulation of IL-1β at early stage after rUCCAO results in poor remyelination after chronic hypoperfusion through blocking OPCs migration. So, IL-1β may serve as a potential therapeutic target for SIVD.