A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS

Lisa Johann, Sasha Soldati, Kristin Müller, Josephine Lampe, Federico Marini, Matthias Klein, Eva Schramm, Nathalie Ries, Carsten Schelmbauer, Ilaria Palagi, Khalad Karram, Julian C. Assmann, Mahtab A. Khan, Jan Wenzel, Mirko H.H. Schmidt, Jakob Körbelin, Dirk Schlüter, Geert van Loo, Tobias Bopp, Britta EngelhardtMarkus Schwaninger, Ari Waisman*

*Corresponding author for this work

Abstract

A20 is a ubiquitin-modifying protein that negatively regulates NF-κB signaling. Mutations in A20/TNFAIP3 are associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (ECs) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. A20ΔCNS-EC mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the blood-brain barrier (BBB) was not impaired, we observed a strong activation of CNS-ECs in these mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We discovered ICOSL to be expressed by A20-deficient CNS-ECs, which we found to function as adhesion molecules. Silencing of ICOSL in CNS microvascular ECs partly reversed the phenotype of A20ΔCNS-EC mice without reaching statistical significance and delayed the onset of EAE symptoms in WT mice. In addition, blocking of ICOSL on primary mouse brain microvascular ECs impaired the adhesion of T cells in vitro. Taken together, we propose that CNS EC-ICOSL contributes to the firm adhesion of T cells to the BBB, promoting their entry into the CNS and eventually driving neuroinflammation.

Original languageEnglish
Article number168314
JournalJournal of Clinical Investigation
Volume133
Issue number24
ISSN0021-9738
DOIs
Publication statusPublished - 01.12.2023

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

  • 205-09 Pharmacology
  • 206-06 Molecular and Cellular Neurology and Neuropathology

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