CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia.
Zimmermann, Julian; Krauthausen, Marius; Hofer, Markus Jet al.
[en] 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.
Disciplines :
Neurology
Author, co-author :
Zimmermann, Julian; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany
Krauthausen, Marius; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany
Hofer, Markus J; Department of Neuropathology, University Clinic of Marburg and Giessen, Marburg, Germany
HENEKA, Michael ; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany ; Clinical Neuroscience Unit, University of Bonn, Bonn, Germany
Campbell, Iain L; School of Molecular Bioscience, University of Sydney, Sydney, Australia
Müller, Marcus; Department of Neurology, Universitätsklinikum Bonn, Bonn, Germany ; School of Molecular Bioscience, University of Sydney, Sydney, Australia
External co-authors :
yes
Language :
English
Title :
CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia.
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