title: Absence of CCL2 and CCL3 Ameliorates Central Nervous System Grey Matter But Not White Matter Demyelination in the Presence of an Intact Blood-Brain Barrier.
abstract: A broad spectrum of diseases is characterized by myelin abnormalities, oligodendrocyte pathology, and concomitant glia activation, among multiple sclerosis (MS). Our knowledge regarding the factors triggering gliosis and demyelination is scanty. Chemokines are pivotal for microglia and astrocyte activation and orchestrate critical steps during the formation of central nervous system (CNS) demyelinating lesions. Redundant functions of chemokines complicate, however, the study of their functional relevance. We used the cuprizone model to study redundant functions of two chemokines, CCL2/MCP1 and CCL3/MIP1α, which are critically involved in the pathological process of cuprizone-induced demyelination. First, we generated a mutant mouse strain lacking functional genes of both chemokines and demonstrated that double-mutant animals are viable, fertile, and do not present with gross abnormalities. Astrocytes and peritoneal macrophages, cultured form tissues of these animals did neither express CCL2 nor CCL3. Exposure to cuprizone resulted in increased CCL2 and CCL3 brain levels in wild-type but not mutant animals. Cuprizone-induced demyelination, oligodendrocyte loss, and astrogliosis were significantly ameliorated in the cortex but not corpus callosum of chemokine-deficient animals. In summary, we provide a novel powerful model to study the redundant function of two important chemokines. Our study reveals that chemokine function in the CNS redounds to region-specific pathophysiological events.
authors: Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
authors: Katharina
authors: K
authors: Janssen
authors: Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
authors: Mira
authors: M
authors: Rickert
authors: Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
authors: Tim
authors: T
authors: Clarner
authors: Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany.
authors: Cordian
authors: C
authors: Beyer
authors: Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Wendlingweg 2, 52074, Aachen, Germany. mkipp@ukaachen.de.|Department of Anatomy II, Ludwig-Maximilians-University of Munich, Munich, Germany. mkipp@ukaachen.de.
authors: Markus
authors: M
authors: Kipp
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D054405:Chemokine CCL3 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D066128:Gray Matter / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014781:Viscera / Q000473:pathology; D066127:White Matter / Q000473:pathology*
chemical_list: C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D003471:Cuprizone
keywords: CNS; Chemokines; Cuprizone; Multiple sclerosis