University of Illinois at Chicago
Browse

File(s) under embargo

1

year(s)

2

month(s)

11

day(s)

until file(s) become available

Investigating the Role of Endothelial Caveolin-1 on T Cell Migration Across the Blood-Brain Barrier

thesis
posted on 2023-08-01, 00:00 authored by Troy N Trevino
Impairment of BBB integrity is a common feature of neuroinflammation and neurodegenerative diseases. Increased expression of Cav-1 on BECs positively correlates with BBB permeability to T cells. However, how Cav-1, a signaling and structural protein in caveolar endocytic vesicles, functions in T cell migration into the CNS is unclear. Here, we tested the role of BEC Cav-1 on T cell BBB transmigration in vitro and in mouse models of Multiple Sclerosis and COVID-19. Our hypothesis is that that brain endothelial Cav-1 promotes T cell migration across the BBB in autoimmune and infectious diseases. We found that Cav-1 deficiency was protective against T cell neuroinflammation in the EAE mouse model of MS and in SARS-CoV-2 respiratory infection. Interestingly, Cav-1-/- mice had fewer CXCR3+ T cells in the CNS during EAE. It's been established that Cav-1 is required for BBB migration of CD4+ Th1 cells, a population known to express the chemokine receptor CXCR3. We found that CXCL10, the chemokine ligand for CXCR3, enhanced Cav-1 dependent transcellular migration of T cell across BECs. Furthermore, we showed that BEC Cav-1 promotes CXCL10 aggregation into cytoplasmic stores to provide local activation of loosely adherent T cells. In COVID-19, age is an important factor in susceptibility to neurological complications resulting respiratory infection. Indeed, we found that aged mice had enhanced BEC expression of Cav-1, increased fibrinogen leakage, and increased T cell neuroinflammation compared to young mice in a SARS-CoV-2 respiratory infection model. RNA sequencing analysis of BECs from COVID-19 mice showed dysregulated Wnt/β-catenin signaling as well as upregulation of inflammatory pathways. Cerebrovascular-targeted activation of Wnt/β-catenin signaling at the BBB in aged SARS-CoV-2 infected mice partially rescued T cell neuroinflammation and neurocognitive dysfunction. Together, these data indicate BEC Cav-1 as a critical regulator of T cell neuroinflammation. Furthermore, modulation of Wnt/β-catenin signaling could be a potential interventional strategy to recover BBB integrity in neuroinflammatory diseases.

History

Advisor

Lutz, Sarah E

Chair

Minshall, Richard D

Department

Anatomy and Cell Biology

Degree Grantor

University of Illinois at Chicago

Degree Level

  • Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Tai, Leon M Shaye, Daniel D Prabhakar, Bellur S

Submitted date

August 2023

Thesis type

application/pdf

Language

  • en

Usage metrics

    Categories

    No categories selected

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC