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Endothelial Caveolin-1 and CXCL10 promote transcellular migration of autoreactive T cells across the blood-brain barrier

View ORCID ProfileTroy N. Trevino, Ali A. Almousawi, Andrea Ochoa-Raya, Kait Zemanski, View ORCID ProfileSuellen DS Oliveira, Felecia M. Marottoli, View ORCID ProfileLeon M. Tai, View ORCID ProfileRichard D. Minshall, View ORCID ProfileSarah E. Lutz
doi: https://doi.org/10.1101/2022.11.15.516689
Troy N. Trevino
1Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
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Ali A. Almousawi
1Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
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Andrea Ochoa-Raya
1Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
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Kait Zemanski
1Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
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Suellen DS Oliveira
2Department of Anesthesiology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
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Felecia M. Marottoli
1Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
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Leon M. Tai
1Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
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Richard D. Minshall
2Department of Anesthesiology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
3Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
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Sarah E. Lutz
1Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
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  • For correspondence: selutz@uic.edu
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Abstract

CXCL10 is an interferon-inducible chemokine that can recruit CXCR3+ leukocytes to the central nervous system, leading to neuroinflammation, demyelination, and neuronal losses. How CXCL10 promotes leukocyte extravasation and diapedesis across the blood-brain barrier – formed by brain endothelial cells – is poorly understood. Here, we report that CXCL10 mediates CD4+ T cell migration through the brain endothelial cell cytoplasm (transcellular), but not cell-cell junctions (paracellular), via the vesicular trafficking protein Caveolin-1. Caveolin-1 promotes CXCL10 aggregation into cytoplasmic stores in brain endothelial cells in vitro to provide the local, high concentration necessary for recruitment of CXCR3+ leukocytes. This process also requires LFA-1 activity. In the absence of Caveolin-1, endothelial CXCL10 is secreted, and the local signaling cues are lost. Consistent with our in vitro data, genetic ablation of Caveolin-1 in endothelial cells reduces the severity of active experimental autoimmune encephalomyelitis (EAE), a murine model for multiple sclerosis, by decreasing the infiltration of CXCR3+ T cells into the CNS. Moreover, loss of Caveolin-1 protects against the adoptive transfer of autoreactive T cells. Our findings establish a novel mechanism by which brain endothelial cells utilize Caveolin-1 dependent CXCL10 intracellular stores to license T cells for transcellular migration across the blood-brain barrier.

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 16, 2022.
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Endothelial Caveolin-1 and CXCL10 promote transcellular migration of autoreactive T cells across the blood-brain barrier
Troy N. Trevino, Ali A. Almousawi, Andrea Ochoa-Raya, Kait Zemanski, Suellen DS Oliveira, Felecia M. Marottoli, Leon M. Tai, Richard D. Minshall, Sarah E. Lutz
bioRxiv 2022.11.15.516689; doi: https://doi.org/10.1101/2022.11.15.516689
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Endothelial Caveolin-1 and CXCL10 promote transcellular migration of autoreactive T cells across the blood-brain barrier
Troy N. Trevino, Ali A. Almousawi, Andrea Ochoa-Raya, Kait Zemanski, Suellen DS Oliveira, Felecia M. Marottoli, Leon M. Tai, Richard D. Minshall, Sarah E. Lutz
bioRxiv 2022.11.15.516689; doi: https://doi.org/10.1101/2022.11.15.516689

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