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

Judith Hauptmann, Lisa Johann, Federico Marini, Maja Kitic, Elisa Colombo, Ilgiz A. Mufazalov, Martin Krueger, Khalad Karram, Sonja Moos, Florian Wanke, Florian C. Kurschus, Matthias Klein, Silvia Cardoso, Judith Strauß, Subhashini Bolisetty, Fred Lühder, Markus Schwaninger, Harald Binder, Ingo Bechman, Tobias BoppAnupam Agarwal, Miguel P. Soares, Tommy Regen*, Ari Waisman

*Corresponding author for this work


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.

Original languageEnglish
JournalActa Neuropathologica
Issue number4
Pages (from-to)549-567
Number of pages19
Publication statusPublished - 01.10.2020

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)


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