Syndecan-1, a Cell Surface Proteoglycan, Negatively Regulates Initial Leukocyte Recruitment to the Brain across the Choroid Plexus in Murine Experimental Autoimmune Encephalomyelitis

Abstract

The cell surface heparan sulfate proteoglycan, syndecan-1, has been reported to be a negative regulator of various inflammatory processes, but its precise mode of action is poorly defined. In this study, we use the murine model of the 35–55 peptide of myelin oligodendrocyte glycoprotein–induced experimental autoimmune encephalomyelitis (EAE), a T lymphocyte–mediated inflammation where the steps in disease development and recovery are well characterized, to decipher how syndecan-1 impacts on the inflammatory reaction. Syndecan-1 knockout (Sdc-1−/−) mice show enhanced disease severity and impaired recovery. The use of bone marrow chimeric mice reveals that both an immune cell and a CNS-resident source of syndecan-1 contribute to this phenotype. Epithelial cells of the choroid plexus, where initial CCL20-induced leukocyte recruitment to the brain occurs, are identified as the predominant site of syndecan-1 expression. Syndecan-1 is lost from this site during the course of EAE by shedding into the cerebrospinal fluid, which correlates with loss of epithelial cell surface–bound CCL20 and is associated with the upregulation of IL-6 expression. In Sdc-1−/− mice, early leukocyte recruitment via the choroid plexus is enhanced, and IL-6 is elevated, which collectively results in higher numbers of the disease inducing Th17 cells in the CNS, thereby contributing to enhanced disease severity. Furthermore, Sdc-1−/− mice have intrinsically elevated plasma cell numbers and higher myelin oligodendrocyte glycoprotein–specific Ab levels during EAE, which we propose contributes to impaired recovery. Our data identify the choroid plexus epithelium as a novel source of IL-6 in EAE and demonstrate that its expression negatively correlates with syndecan-1 expression at this site.

Clinical implications of leukocyte infiltration at the choroid plexus in (neuro)inflammatory disorders

“…This polarized localization of these adhesion molecules at the CPE indicates its importance in immunosurveillance [20,33]. Syndecan-1 (CD138) is a cell-surface heparin sulfate proteoglycan expressed by epithelial cells, such as the CPE [76]. It modulates the activity of chemokines, cytokines, integrins, selectins, and other adhesion molecules, and is assumed to be a negative regulator of various inflammatory processes [76,77].…”

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

“…Adhesion molecules, such as intercellular adhesion molecule 1 (ICAM1) and P-selectin, are expressed in the choroid plexus at baseline, providing a permissive environment for immune-cell infiltration (Baruch et al, 2015;Kivisakk et al, 2003). 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).…”

“…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).…”

“…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). During autoimmune encephalitis, syndecan is shed from the choroid plexus epithelium into the CSF, where it acts like a sponge to bind released chemokines, thus sequestering them from accumulating lymphocytes (Zhang et al, 2013).…”

“…A new study, using rats with experimental autoimmune encephalomyelitis (EAE) as a model, indeed points to the meningeal blood vessels as the main site for immune-cell trafficking at specific time points during EAE development (Schlager et al, 2016). One possibility is that at certain time points during the inflammatory process, infiltration through the choroid plexus is regulated via specific pathways (such as those mediated by CCR6 or syndecan) (Reboldi et al, 2009;Zhang et al, 2013). It seems, however, that more thorough characterization of the immune responses in each compartment of the CNS is needed.…”