Journal
ACTA NEUROPATHOLOGICA
Volume 140, Issue 4, Pages 549-567Publisher
SPRINGER
DOI: 10.1007/s00401-020-02187-x
Keywords
Blood-brain barrier; Interleukin-1; Autoimmunity; Experimental autoimmune encephalomyelitis (EAE); Heme oxygenase-1 (HO-1)
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Funding
- Projekt DEAL
- National Multiple Sclerosis Society [RG-1707-28780]
- Sobek Foundation
- Hertie Foundation [P1150062]
- Institutional Funding (Level I) of the University Medical Center Mainz
- Deutsche Forschungsgemeinschaft (DFG) [CRC/TRR128, CRC1292]
- Focus Program Translational Neuroscience (FTN) of the Johannes Gutenberg University Mainz
- Gulbenkian [HR1800502]
- La Caixa [HR1800502]
- Bill & Melinda Gates Foundation [OPP1148170]
- FCT [5723/2014, FEDER029411]
- National Institutes of Health [R01 DK059600, P30 DK079337, R01 DK118932]
- National Institute of Health [K01 DK103931]
- American Society of Nephrology (Carl W. Gottschalk Research Scholar Grant)
- Bill and Melinda Gates Foundation [OPP1148170] Funding Source: Bill and Melinda Gates Foundation
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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 genesVcam1,Icam1andAckr1(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.
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