Host Immune Signals Regulate Blood-Brain Barrier Function During Central Nervous System Infection and Autoimmunity

A major hallmark of neuroinflammatory diseases is the breakdown of the blood-brain barrier (BBB). This barrier between the hematogenous circulation and the parenchyma of the central nervous system (CNS) is a multicellular interface made up of endothelial cells joined by tight and adherens junctions (TJs and AJs), along with pericytes and the endfeet projections of astroglia. Together, these cells tightly restrict the movement of solutes and cells from the circulation into the CNS in a manner crucial for proper CNS homeostasis. Regulation of BBB function occurs dynamically during neuroinflammatory diseases such as infection and CNS autoimmunity, resulting in both protective and pathologic outcomes. In this dissertation, we describe several novel cellular and molecular mechanisms of immune mediated control of BBB function. In particular, these studies further our understanding of how host cytokines and chemokines function at the BBB during disease, impacting essential features of BBB physiology including junction integrity, endothelial polarity, chemokine localization, and paracellular permeability. Importantly, our studies demonstrate that cytokine/chemokine effects at the BBB are consequential to the pathogenesis of neuroinflammatory diseases, including the CNS infiltration of autoreactive leukocytes during autoimmunity, as well as the neuroinvasive potential of West Nile virus, an emerging neurotropic pathogen. Thus, this work highlights new possibilities for targeted therapeutics for human diseases that involve BBB dysfunction. Specifically, we identify S1PR2 as a disease modifying molecule in multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE). Our studies demonstrate that S1PR2 signaling in CNS vascular endothelia contributes to diminished integrity of AJs, resulting in enhanced BBB permeability and loss of polarized expression of the chemokine CXCL12 along basolateral vessel surfaces, resulting in enhanced parenchymal infiltration of leukocytes, increased lesion formation, and poorer clinical outcome during EAE. In addition, our studies establish a link between sexually dimorphic expression of S1PR2 in disease susceptible regions of the CNS in female mice and women with MS to enhanced susceptibility to CNS autoimmunity. These findings offer exciting new clues as to the mechanisms underlying sex bias in CNS autoimmunity and identify a new target for therapeutic interventions at the BBB. Other studies identified novel protective functions for type I and III interferons (IFNs) at the BBB during WNV infection. Our studies suggest that expression of innate IFNs following recognition of WNV pathogen associated molecular patterns results in enhanced BBB integrity. Type I IFNs are shown to be a key regulator of BBB integrity by preserving TJ integrity and endothelial permeability, thereby limiting the ability of WNV to traffic across the BBB. This effect was accomplished via direct signaling mechanisms, as well as by suppression of inflammatory cytokine signals that permeabilize the BBB. Further studies revealed that the type III IFNs display similar properties to type I IFNs at the BBB, restricting the neuroinvasive capacity of WNV by enhancing BBB integrity. As type III IFN receptor expression is more highly localized to tissue barriers compared to type I IFNs, these studies suggest new therapeutic opportunities for IFN therapy in the treatment of neuroinflammatory disease