Interleukin-1 promotes autoimmune neuroinflammation by suppressing endothelial heme oxygenase-1 at the blood\u2013brain barrier

Judith Hauptmann,Fred Lühder,Markus Schwaninger,Lisa Johann,Ingo Bechman,Ilgiz A Mufazalov,Subhashini Bolisetty,Matthias Klein,Tommy Regen,Fédérico Marini ,E Colombo ,Sílvia Cardoso ,Johannes Strauß ,Martin Krueger ,Khalad Karram,Ari Waisman,Maja Kitic,Harald Binder,Tobias Bopp,Miguel P Soares,Sonja Moos,Florian C Kurschus,Anupam Agarwal,Florian Wanke

doi:10.1007/s00401-020-02187-x

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.

Highlights

The inflammatory disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are characterized by peripheral immune cell infiltration into the central nervous system (CNS), which leads to demyelination and axonal damage in the brain and spinal cord [38]
In accordance with published data [39], we observed that 15% of blood–brain barrier (BBB)-endothelial cells (ECs) expressed the IL-1 receptor type 1 (IL-1R1) as early as 3 days post-immunization (Supplementary Fig. 1a–c, online resource) as a result of innate activation caused by the CFA injection (Supplementary Fig. 2, online resource)
Using transgenic mouse lines in which Il1r1 is deleted in specific CNS cellular subsets, we show that interleukin 1 (IL-1) signaling in astrocytes and microglia is dispensable for the pathogenesis of EAE

Summary

Introduction

The inflammatory disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are characterized by peripheral immune cell infiltration into the central nervous system (CNS), which leads to demyelination and axonal damage in the brain and spinal cord [38]. Extended author information available on the last page of the article consequence of focal blood–brain barrier (BBB) breakdown, which enables the uncontrolled influx of peripheral cells and molecules. The BBB is a tightly regulated vascular barrier, composed of specialized endothelial cells (ECs), connected through intercellular tight junctions and adherens junctions, thereby controlling traffic of cells and molecules across the BBB [79]. Disorganization of these junctional proteins together with upregulation of cell adhesion molecules, such as intercellular adhesion molecule-1 (Icam-1) and vascular adhesion molecule-1 (Vcam-1), is associated with peripheral cell adhesion and migration into the CNS in MS and EAE [7].

Objectives

Methods

Results

Conclusion