CXCL10 triggers early microglial activation in the cuprizone model.
A broad spectrum of diseases is characterized by myelin abnormalities and/or oligodendrocyte pathology. In most, if not all, of these diseases, early activation of microglia occurs. Our knowledge regarding the factors triggering early microglia activation is, however, incomplete. In this study, we used the cuprizone model to investigate the temporal and causal relationship of oligodendrocyte apoptosis and early microglia activation. Genome-wide gene expression studies revealed the induction of distinct chemokines, among them Cxcl10, Ccl2, and Ccl3 in cuprizone-mediated oligodendrocyte apoptosis. Early microglia activation was unchanged in CCL2- and CCL3-deficient knockouts, but was significantly reduced in CXCL10-deficient mice, resulting in an amelioration of cuprizone toxicity at later time points. Subsequent in vitro experiments revealed that recombinant CXCL10 induced migration and a proinflammatory phenotype in cultured microglia, without affecting their phagocytic activity or proliferation. In situ hybridization analyses suggest that Cxcl10 mRNA is mainly expressed by astrocytes, but also oligodendrocytes, in short-term cuprizone-exposed mice. Our results show that CXCL10 actively participates in the initiation of microglial activation. These findings have implications for the role of CXCL10 as an important mediator during the initiation of neuroinflammatory processes associated with oligodendrocyte pathology.
Faculty of Medicine, Institute of Neuroanatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany;
Tim
T
Clarner
Faculty of Medicine, Institute of Neuroanatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany;
Katharina
K
Janssen
Faculty of Medicine, Institute of Neuroanatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany;
Lara
L
Nellessen
Department of Neurology, Clinical Neuroimmunology and Neurochemistry, Hannover Medical School, 30625 Hannover, Germany;
Martin
M
Stangel
Department of Neurology, Clinical Neuroimmunology and Neurochemistry, Hannover Medical School, 30625 Hannover, Germany;
Thomas
T
Skripuletz
Faculty of Medicine, Institute of Neuroanatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany;
Barbara
B
Krauspe
Faculty of Medicine, Institute of Pharmacology and Toxicology, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany;
Franz-Martin
FM
Hess
Interdisciplinary Centre for Clinical Research Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany;
Bernd
B
Denecke
Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany;
Clara
C
Beutner
Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany;
Bettina
B
Linnartz-Gerlach
Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany;
Harald
H
Neumann
Department of Neurosciences, Laval University Hospital Research Center, Quebec City G1V 4G2, Quebec, Canada;
Luc
L
Vallières
Department of Pathology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands;
Sandra
S
Amor
Department of Pediatrics, Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany; and.
Kim
K
Ohl
Department of Pediatrics, Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany; and.
Klaus
K
Tenbrock
Faculty of Medicine, Institute of Neuroanatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany;
Cordian
C
Beyer
Faculty of Medicine, Institute of Neuroanatomy, Rheinisch-Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany; Department of Anatomy II, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany mkipp@ukaachen.de.
Markus
M
Kipp
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054357:Chemokine CXCL10 / Q000235:genetics*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003471:Cuprizone / Q000008:administration & dosage / Q000494:pharmacology*; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D045022:Lactate Dehydrogenases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D009836:Oligodendroglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D051381:Rats
D054357:Chemokine CXCL10; D018925:Chemokines; D003471:Cuprizone; D045022:Lactate Dehydrogenases