Authors:	Hauptmann, Judith Johann, Lisa Marini, Federico Kitic, Maja Colombo, Elisa Mufazalov, Ilgiz A. Krueger, Martin Karram, Khalad Moos, Sonja Wanke, Florian Kurschus, Florian C. Klein, Matthias Cardoso, Silvia Strauß, Judith Bolisetty, Subhashini Lühder, Fred Schwaninger, Markus Binder, Harald Bechman, Ingo Bopp, Tobias Agarwal, Anupam Soares, Miguel P. Regen, Tommy Waisman, Ari
Title:	Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood–brain barrier
Online publication date:	7-May-2021
Year of first publication:	2020
Language:	english
Abstract:	The proinflammatory cytokine interleukin 1 (IL-1) is crucially involved in the pathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Herein, we studied the role of IL-1 signaling in blood–brain barrier (BBB) endothelial cells (ECs), astrocytes and microglia for EAE development, using mice with the conditional deletion of its signaling receptor IL-1R1. We found that IL-1 signaling in microglia and astrocytes is redundant for the development of EAE, whereas the IL-1R1 deletion in BBB-ECs markedly ameliorated disease severity. IL-1 signaling in BBB-ECs upregulated the expression of the adhesion molecules Vcam-1, Icam-1 and the chemokine receptor Darc, all of which have been previously shown to promote CNS-specific inflammation. In contrast, IL-1R1 signaling suppressed the expression of the stress-responsive heme catabolizing enzyme heme oxygenase-1 (HO-1) in BBB-ECs, promoting disease progression via a mechanism associated with deregulated expression of the IL-1-responsive genes Vcam1, Icam1 and Ackr1 (Darc). Mechanistically, our data emphasize a functional crosstalk of BBB-EC IL-1 signaling and HO-1, controlling the transcription of downstream proinflammatory genes promoting the pathogenesis of autoimmune neuroinflammation.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-5779
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	Acta neuropathologica 140
Pages or article number:	549 567
Publisher:	Springer
Publisher place:	Berlin u.a.
Issue date:	2020
ISSN:	1432-0533
Publisher URL:	https://doi.org/10.1007/s00401-020-02187-x
Publisher DOI:	10.1007/s00401-020-02187-x
Appears in collections:	JGU-Publikationen