2. Academic Validation
  3. A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS

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

  • J Clin Invest. 2023 Dec 15;133(24):e168314. doi: 10.1172/JCI168314.
Lisa Johann 1,  Sasha Soldati 2,  Kristin Müller 3,  Josephine Lampe 3 4,  Federico Marini 5 6,  Matthias Klein 7,  Eva Schramm 1,  Nathalie Ries 1,  Carsten Schelmbauer 1,  Ilaria Palagi 1,  Khalad Karram 1,  Julian C Assmann 3,  Mahtab A Khan 3,  Jan Wenzel 3 4,  Mirko Hh Schmidt 8,  Jakob Körbelin 9,  Dirk Schlüter 10,  Geert van Loo 11 12,  Tobias Bopp 6 7,  Britta Engelhardt 2,  Markus Schwaninger 3 4,  Ari Waisman 1 6
Affiliations

Affiliations

  • 1 Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany.
  • 2 Theodor Kocher Institute, University of Bern, Bern, Switzerland.
  • 3 Institute for Experimental and Clinical Pharmacology and Toxicology, Center of Brain, Behavior and Metabolism (CBBM), University of Lübeck, Lübeck, Germany.
  • 4 DZHK (German Research Centre for Cardiovascular Research), Hamburg-Lübeck-Kiel, Germany.
  • 5 Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI).
  • 6 Research Center for Immunotherapy (FZI), and.
  • 7 Institute for Immunology, University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany.
  • 8 Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, Dresden, Germany.
  • 9 University Medical Center Hamburg-Eppendorf, Department of Oncology, Hematology and Bone Marrow Transplantation, Hamburg, Germany.
  • 10 Hannover Medical School, Institute of Medical Microbiology and Hospital Epidemiology, Hannover, Germany.
  • 11 Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 12 VIB-UGent Center for Inflammation Research, Ghent, Belgium.
PMID: 37856217 DOI: 10.1172/JCI168314
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.

Keywords

Autoimmunity; Endothelial cells; Mouse models; Multiple sclerosis; Neuroscience.

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