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 language | English |
|---|---|
| Article number | 168314 |
| Journal | Journal of Clinical Investigation |
| Volume | 133 |
| Issue number | 24 |
| ISSN | 0021-9738 |
| DOIs | |
| Publication status | Published - 01.12.2023 |
Funding
We would like to thank Ralf Adams for allowing us to use the Cdh5-CreERT2 mice. We further thank Sara Barcos for excellent technical assistance and Natalia Soshnikova for helping with cDNA preparation for sequencing. We would like to thank Tommy Regen, Katlynn Carter, Rebecca Jasser, Elisa Blickberndt, and Michaela Blanfeld for helping with the experiments. Work was supported by the computing infrastructure provided by the Core Facility Bioinformatics and the Core Facility Flow Cytometry (CFFC) at the University Medical Center Mainz. Graphical abstract was created with BioRender.com. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project number 318346496 – SFB1292/2 to FM, TB, and AW, project number 490846870 – TRR355/1 to AW and TB, and SCHW 416/5-3 to MS. AW was also supported by the DFG grant number 446267576 under the Reinhart Koselleck program. This work was further funded with an unrestricted grant from Roche Global Neuroscience, Basel, Switzerland.
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
- 2.22-09 Pharmacology
- 2.23-06 Molecular and Cellular Neurology and Neuropathology
