RT Journal Article
SR Electronic
T1 Endothelial Caveolin-1 and CXCL10 promote transcellular migration of autoreactive T cells across the blood-brain barrier
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.15.516689
DO 10.1101/2022.11.15.516689
A1 Troy N. Trevino
A1 Ali A. Almousawi
A1 Andrea Ochoa-Raya
A1 Kait Zemanski
A1 Suellen DS Oliveira
A1 Felecia M. Marottoli
A1 Leon M. Tai
A1 Richard D. Minshall
A1 Sarah E. Lutz
YR 2022
UL http://biorxiv.org/content/early/2022/11/16/2022.11.15.516689.abstract
AB 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 StatementThe authors have declared no competing interest.