title: IL-17A Promotes Granulocyte Infiltration, Myelin Loss, Microglia Activation, and Behavioral Deficits During Cuprizone-Induced Demyelination.
abstract: Recent evidence suggests a pivotal role of the proinflammatory cytokine interleukin - 17A (IL-17) in demyelinating autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS). Nevertheless, it remains unclear if this cytokine exerts direct effects on CNS resident cells during MS or modulates the function of infiltrating immune cells towards a more detrimental phenotype. Here, we investigated the effects of locally produced IL-17 during experimental demyelination of the CNS using the cuprizone (CPZ) model in mice with (GF/IL17) or without transgenic production of IL-17 by astrocytes in the CNS. During early demyelination, GF/IL17 mice demonstrated enhanced activity and decreased anxiety-related behavior in the elevated plus maze suggesting a more severe disease course. Furthermore, in GF/IL17 mice, toxic demyelination was accelerated and synthesis of myelin proteins was reduced. Early demyelination was accompanied by an increased ratio of infiltrating granulocytes in GF/ILl17 mice. The presence of IL-17 during CPZ treatment increased the accumulation of activated microglia and sustained microglial proliferation during myelin loss. Taken together, our results argue for a detrimental role of IL-17 during demyelinating diseases.
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str 25, 53127, Bonn, Germany. julian.zimmermann@ukb.uni-bonn.de.
authors.forename: Julian
authors.identifier: 0000-0003-1964-0078
authors.initials: J
authors.lastname: Zimmermann
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str 25, 53127, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Emrich
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str 25, 53127, Bonn, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Krauthausen
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str 25, 53127, Bonn, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Saxe
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str 25, 53127, Bonn, Germany.
authors.forename: Louisa
authors.initials: L
authors.lastname: Nitsch
authors.affiliation: Clinical Neurosciences, Department of Neurology, University of Bonn, Bonn, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia.
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.affiliation: Department of Neurology, University of Bonn, Sigmund-Freud-Str 25, 53127, Bonn, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Müller
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000473:pathology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D020381:Interleukin-17; D003471:Cuprizone
keywords: Cuprizone; Cytokines; Demyelination; Granulocytes; Interleukin-17; Myelin