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 Hh Schmidt
  • Jakob Körbelin
  • Dirk Schlüter
  • Geert van Loo
  • Tobias Bopp
  • Britta Engelhardt
  • Markus Schwaninger
  • Ari Waisman

Beteiligte Einrichtungen

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.

Bibliografische Daten

OriginalspracheEnglisch
Aufsatznummere168314
ISSN0021-9738
DOIs
StatusVeröffentlicht - 15.12.2023
PubMed 37856217