Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood-brain barrier.

Autor: Hauptmann J; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Johann L; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Marini F; Center of Thrombosis and Hemostasis Mainz (CTH), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Kitic M; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Colombo E; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Mufazalov IA; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Krueger M; Anatomical Institute, University of Leipzig, Leipzig, Germany., Karram K; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Moos S; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Department of Dermatology, Heidelberg University Hospital, 69120, Heidelberg, Germany., Wanke F; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Immunology, Infectious Diseases and Ophthalmology (I2O) Discovery and Translational Area Roche Innovation Center, Basel, Switzerland., Kurschus FC; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Department of Dermatology, Heidelberg University Hospital, 69120, Heidelberg, Germany., Klein M; Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Cardoso S; Instituto Gulbenkian de Ciência, Oeiras, Portugal., Strauß J; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany., Bolisetty S; Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany., Lühder F; Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen, Göttingen, Germany., Schwaninger M; Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany., Binder H; Institute of Medical Biometry and Statistics, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany., Bechman I; Anatomical Institute, University of Leipzig, Leipzig, Germany., Bopp T; Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.; Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany., Agarwal A; Nephrology Research and Training Center, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Soares MP; Instituto Gulbenkian de Ciência, Oeiras, Portugal., Regen T; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. regen@uni-mainz.de., Waisman A; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. waisman@uni-mainz.de.; Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. waisman@uni-mainz.de.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2020 Oct; Vol. 140 (4), pp. 549-567. Date of Electronic Publication: 2020 Jul 11.
DOI: 10.1007/s00401-020-02187-x
Abstrakt: 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.
Databáze: MEDLINE
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