Johann, Lisa; Soldati, Sasha; Müller, Kristin; Lampe, Josephine; Marini, Federico; Klein, Matthias; Schramm, Eva; Ries, Nathalie; Schelmbauer, Carsten; Palagi, Ilaria; Karram, Khalad; Assmann, Julian C; Khan, Mahtab A; Wenzel, Jan; Schmidt, Mirko Hh; Körbelin, Jakob; Schlüter, Dirk; van Loo, Geert; Bopp, Tobias; Engelhardt, Britta; ... (2023). A20 regulates lymphocyte adhesion in murine neuroinflammation by restricting endothelial ICOSL expression in the CNS. The journal of clinical investigation, 133(24) American Society for Clinical Investigation 10.1172/JCI168314
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168314.1-20231019091134-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf - Accepted Version Available under License Creative Commons: Attribution (CC-BY). Download (5MB) | Preview |
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. A20∆CNS-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 as adhesion molecule expressed by A20-deficient CNS-ECs. Silencing of ICOSL in CNS microvascular ECs partly reversed the phenotype of A20∆CNS-EC mice without reaching statistical significance and delayed the onset of EAE symptoms in wildtype mice. In addition, blocking of ICOSL on primary mouse brain microvascular endothelial cells (pMBMECs) impaired the adhesion of T cells in vitro. Taken together, we here 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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute |
UniBE Contributor: |
Soldati, Sasha Giulio Natale, Engelhardt, Britta |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1558-8238 |
Publisher: |
American Society for Clinical Investigation |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
20 Oct 2023 08:48 |
Last Modified: |
16 Dec 2023 00:14 |
Publisher DOI: |
10.1172/JCI168314 |
PubMed ID: |
37856217 |
Uncontrolled Keywords: |
Autoimmunity Endothelial cells Mouse models Multiple sclerosis Neuroscience |
BORIS DOI: |
10.48350/187315 |
URI: |
https://boris.unibe.ch/id/eprint/187315 |
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