Alterations in Tight Junction Protein and IgG Permeability Accompany Leukocyte Extravasation Across the Choroid Plexus During Neuroinflammation

Abstract

The choroid plexus (CP) is considered to be a point of leukocyte entry into the CNS during normal immune surveillance and in neuroinflammatory diseases. The structural and functional alterations within the CP that support this migration are not understood. We used quantitative, high-resolution, 3-dimensional (3-D) fluorescence imaging to analyze CP alterations associated with inflammatory responses in C57/Bl6 mice after the induction of experimental autoimmune encephalomyelitis by immunization with myelin oligodendrocyte glycoprotein (MOG) and complete Freund adjuvant/pertussis toxin (MOG-CFA/PTX) or adjuvants alone (CFA-PTX). The MOG-CFA/PTX and CFA/PTX produced similar effects, although those caused by the former were consistently more marked. Both treatments resulted in the accumulation of serum immunoglobulin G and leukocytes in the CP stroma, consistent with elevated stromal capillary permeability. They also provoked distortions and diminished immunostaining patterns of the tight junction adaptor protein ZO-1 in the choroidal epithelium but no obvious change in the patterns of the tight junction associated protein claudin-2. Only MOG-CFA/PTX triggered visible extravasation of immunoglobulin G and leukocytes across the choroidal epithelium. Our results suggest that CFA/PTX primes the CP for neuroinflammation by inducing structural changes that are exacerbated when there is an immune response to MOG and reinforce the CP as a gateway for leukocytes to enter the CNS by accessing the CSF and leptomeninges.

Therapeutic implications of the choroid plexus–cerebrospinal fluid interface in neuropsychiatric disorders

“…The CP plays a pivotal role in neural function by maintaining brain homeostasis, surveying the immunological status of the brain, and participating in inflammatory processes and repair following trauma (Aube et al, 2014;Szmydynger-Chodobska et al, 2009Shechter et al, 2013;Shrestha et al, 2014;Simard et al, 2011). Even modest structural and/or functional changes of the CP can have significant effects and have been linked to several central nervous system (CNS) diseases and trauma (Aube et al, 2014;Szmydynger-Chodobska et al, 2009Shechter et al, 2013;Shrestha et al, 2014;Simard et al, 2011). The BCSFB responds basolaterally to the blood side and apically to the cerebrospinal fluid (CSF) side, hence, it forms a well-positioned interface between periphery and CNS.…”

Central Nervous System: (Immunological) Ivory Tower or Not?

“…As a result, peripheral stimuli in the choroid plexus normally dictate the entry of only a limited, nonantigen-specific immune-cell infiltrate into the CSF (Petito and Adkins, 2005;Shrestha et al, 2014;Young et al, 2011). Under autoimmune conditions, however, entry of the infiltrate is more extensive (Giunti et al, 2003;Shrestha et al, 2014). In addition to the temporal regulation (whose mechanisms are as yet unknown), other mechanisms, such as shedding of syndecans, may limit the extent of the choroid plexus infiltrate (Zhang et al, 2013).…”

“…'Activation' of the choroid plexus usually refers to upregulation of inflammatory cytokines (such as IL-1β, TNFα, and IL-6), as well as upregulation of adhesion molecules and downregulation of tight junction molecules (Marques et al, 2007(Marques et al, , 2009Shrestha et al, 2014;Young et al, 2011). Interestingly, the inflammatory response to peripheral stimuli in the choroid plexus is much weaker than in other organs in the periphery (liver, spleen) and is subjected to tight temporal regulation, usually resolving within 24 h of the stimulus (Marques et al, 2009;Shrestha et al, 2014).…”

“…The levels of such adhesion molecules, as well as of tight junction components, are dynamically controlled by the cytokine milieu and inflammatory stimuli to regulate the amounts of cell traffic into the CSF (Baruch et al, 2015;Kunis et al, 2013;Marques et al, 2009;Zhang et al, 2013). Inflammatory stimuli, such as peripheral infection or autoimmune diseases, are usually 'activators' of the choroid plexus (Marques et al, 2007(Marques et al, , 2009Petito and Adkins, 2005;Reboldi et al, 2009;Shrestha et al, 2014;Young et al, 2011;Zhang et al, 2013). In contrast, an aging milieu renders the site more quiescent for immune-cell trafficking (Baruch et al, , 2015Mesquita et al, 2015).…”

“…Interestingly, the inflammatory response to peripheral stimuli in the choroid plexus is much weaker than in other organs in the periphery (liver, spleen) and is subjected to tight temporal regulation, usually resolving within 24 h of the stimulus (Marques et al, 2009;Shrestha et al, 2014). As a result, peripheral stimuli in the choroid plexus normally dictate the entry of only a limited, nonantigen-specific immune-cell infiltrate into the CSF (Petito and Adkins, 2005;Shrestha et al, 2014;Young et al, 2011). Under autoimmune conditions, however, entry of the infiltrate is more extensive (Giunti et al, 2003;Shrestha et al, 2014).…”