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

Animals Blood-Brain Barrier / enzymology Encephalomyelitis, Autoimmune, Experimental / enzymology Endothelial Cells / enzymology Gene Expression Regulation / immunology Heme Oxygenase-1 / metabolism Inflammation / immunology Interleukin-1 / immunology Mice Mice, Inbred C57BL Signal Transduction / immunology

Autoimmunity Blood–brain barrier Experimental autoimmune encephalomyelitis (EAE) Heme oxygenase-1 (HO-1) Interleukin-1

Journal

Acta neuropathologica

ISSN: 1432-0533

Titre abrégé: Acta Neuropathol

Pays: Germany

ID NLM: 0412041

Informations de publication

Date de publication:
10 2020

Historique:

received: 10 03 2020

accepted: 26 06 2020

revised: 05 06 2020

pubmed: 12 7 2020

medline: 1 6 2021

entrez: 12 7 2020

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1007/s00401-020-02187-x PMID: 32651669 PMC: PMC7498485

pubmed: 32651669

doi: 10.1007/s00401-020-02187-x

pii: 10.1007/s00401-020-02187-x

pmc: PMC7498485

doi:

Substances chimiques

Interleukin-1 0

Heme Oxygenase-1 EC 1.14.14.18

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

549-567

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