Interleukin-1β impedes oligodendrocyte progenitor cell recruitment and white matter repair following chronic cerebral hypoperfusion.
Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion exhibits progressive white matter and cognitive impairments. However, its pathogenetic mechanisms are poorly understood. We investigated the role of interleukin-1β (IL-1β) and its receptor IL-1 receptor type 1 (IL-1R1) in an experimental SIVD model generated via right unilateral common carotid arteries occlusion (rUCCAO) in mice. We found that IL-1β expression was elevated in the corpus callosum at the early stages after rUCCAO. IL-1 receptor antagonist (IL-1Ra), when delivered at an early stage, as well as IL-1R1 knockout, rescued the downregulation of myelin basic protein (MBP) and improved remyelination at the later stage after rUCCAO. Our data suggest that the recruitment of OPCs, but not the proliferation or differentiation of OPCs, is the only compromised step of remyelination following chronic cerebral ischemia. IL-1Ra treatment and IL-1R1 knockout had no effect on the oligodendrocyte progenitor cell (OPC) proliferation, but did promote the recruitment of newly generated OPCs to the corpus callosum, which can be reversed by compensatory expression of IL-1R1 in the SVZ of IL-1R1 knockout mice. Further, we found that recruited OPCs contribute to oligodendrocyte regeneration and functional recovery. In transwell assays, IL-1β inhibited OPC migration through IL-1R1. Moreover, KdPT which can enter the brain to block IL-1R1 also showed comparable protection when intraperitoneally delivered. Our results suggest that IL-1β during the early stages following chronic cerebral hypoperfusion impedes OPC recruitment via IL-1R1, which inhibits white matter repair and functional recovery. IL-1R1 inhibitors may have potential uses in the treatment of SIVD.
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
Yiting
Y
Zhou
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Department of Pharmacy, Sir Run Run Shaw Hospital, 3 East Qingchun Road, Hangzhou, Zhejiang 310016, PR China.
Jing
J
Zhang
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
Lu
L
Wang
Department of Pharmacy, Sir Run Run Shaw Hospital, 3 East Qingchun Road, Hangzhou, Zhejiang 310016, PR China.
Ying
Y
Chen
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
Yushan
Y
Wan
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
Yang
Y
He
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
Lei
L
Jiang
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
Jing
J
Ma
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
Rujia
R
Liao
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, PR China.
Xiangnan
X
Zhang
Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, PR China.
Liyun
L
Shi
Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Soochow University School of Pharmaceutical Science, Suzhou 215123, PR China.
Zhenghong
Z
Qin
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China.
Yudong
Y
Zhou
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, PR China. Electronic address: chenzhong@zju.edu.cn.
Zhong
Z
Chen
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, College of Pharmaceutical Sciences, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, PR China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, PR China. Electronic address: huww@zju.edu.cn.
Weiwei
W
Hu
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D053583:Interleukin-1beta / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology; D000073637:Oligodendrocyte Precursor Cells / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D066127:White Matter / Q000378:metabolism* / Q000473:pathology
D053583:Interleukin-1beta
Chronic cerebral hypoperfusion; IL-1 receptor type 1 (IL-1R1); Interleukin-1β (IL-1β); Oligodendrocyte progenitor cells (OPCs); Recruitment; White matter