title: CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia.
abstract: Interleukin-17A (IL-17A) is a key cytokine modulating the course of inflammatory diseases. Whereas effector functions of IL-17A like induction of antimicrobial peptides and leukocyte infiltration could clearly be demonstrated for peripheral organs, CNS specific effects are not well defined and appear controversial. To further clarify the functional significance of IL-17A in the CNS, we generated a transgenic mouse line with astrocyte-restricted expression of the IL-17A gene. GFAP/IL-17A transgenic mice develop normally and do not show any signs of neurological dysfunction. However, histological characterization revealed astrocytosis and activation of microglia. Demyelination, neurodegeneration or prominent tissue damage was not observed but a vascular pathology mimicking microangiopathic features was evident. Histological and flow cytometric analysis demonstrated the absence of parenchymal infiltration of immune cells into the CNS of GFAP/IL-17A transgenic mice. In GFAP/IL-17A mice, LPS-induced endotoxemia led to a more pronounced microglial activation with expansion of a distinct CD45(high)/CD11b(+) population and increased induction of proinflammatory cytokines compared with controls. Our data argues against a direct role of IL-17A in mediating tissue damage during neuroinflammation. More likely IL-17A acts as a modulating factor in the network of induced cytokines. This novel mouse model will be a very useful tool to further characterize the role of IL-17A in neuroinflammatory disease models.
authors.affiliation: Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Zimmermann
authors.forename: Marius
authors.initials: M
authors.lastname: Krauthausen
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Hofer
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.forename: Marcus
authors.initials: M
authors.lastname: Müller
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D019446:Endotoxemia / Q000473:pathology*; D005434:Flow Cytometry; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D007249:Inflammation / Q000473:pathology*; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D055806:Microvessels / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005904:Glial Fibrillary Acidic Protein; D020381:Interleukin-17