Cell Adhesion & Migration 6:5, 390–396; September/October 2012; G 2012 Landes Bioscience Cell trafficking through the choroid plexus Rick B. Meeker,1,2,* Kimberly Williams,1,2 Deirdre A. Killebrew1 and Lola C. Hudson3 1Department of Neurology; University of North Carolina, Chapel Hill; Chapel Hill, NC USA; 2Curriculum in Neurobiology; University of North Carolina, Chapel Hill; Chapel Hill, NC USA; 3Department of Molecular Biomedical Sciences; College of Veterinary Medicine; North Carolina State University; Raleigh, NC USA he choroid plexus is a multifunc- fluid (CSF). On average, normal CSF T tional organ that sits at the contains about 1.12 white blood cells/ml1 interface between the blood and cere- with approximately 500,000 immune cells brospinal fluid (CSF). It serves as a trafficking through the ventricles each day. gateway for immune cell trafficking into Within the CNS, specialized tissue inter- the CSF and is in an excellent position to faces and intrinsic factors play a prominent provide continuous immune surveillance role in the control of this trafficking and by CD4+ T cells, macrophages and the development of inflammatory dendritic cells and to regulate immune responses. These interfaces include the cell trafficking in response to disease and blood-brain barrier, the choroid plexus trauma. However, little is known about and the meningeal vasculature. While the mechanisms that control trafficking considerable attention has been paid to through this structure. Three cell types immune cell interactions at the blood- within the choroid plexus, in particular, brain barrier, fewer studies have focused Keywords: cerebrospinal fluid, pleocytosis, may play prominent roles in controlling on the role of the blood-cerebrospinal fluid monocytes, macrophages, dendritic cells, the development of immune responses barrier within the choroid plexus and T cells, inflammation, adhesion molecules, within the nervous system: the epithelial meninges.2-4 The limited knowledge of chemokines cells, which form the blood-CSF the control of immune cell trafficking at barrier, and resident macrophages and the blood-CSF barrier stands in stark Abbreviations: CNS, central nervous dendritic cells in the stromal matrix. contrast to the widespread use of CSF system; CSF, cerebrospinal fluid; EAE, Adhesion molecule and chemokine leukocyte pleocytosis in clinical studies to experimental autoimmune expression by the epithelial cells allows evaluate inflammation in the CNS. encephalomyelitis; HIV, human substantial control over the selection of Available evidence clearly indicates that immunodeficiency virus; ICAM, cells that transmigrate. Macrophages the choroid plexus has many unique intercellular adhesion molecule; and dendritic cells can present antigen features such as abundant dendritic cells,5 MadCAM, mucosal addressin cell within the choroid plexus and/or trans- macrophages6 and patterns of epithelial adhesion molecule; MS, multiple sclerosis; migrate into the cerebral ventricles to adhesion molecule expression7 that sup- VCAM, vascular cell adhesion molecule serve a variety of possible immune port continuous immunosurveillance1,8,9 as functions. Studies to better understand well as the ability to regulate cell activation Submitted: 04/30/12 the diverse functions of these cells are and trafficking in response to pathological Revised: 06/07/12 likely to reveal new insights that foster insults.8,10 However, many outstanding Accepted: 06/08/12 the development of novel pharmaco- questions remain regarding the regulation logical and macrophage-based interven- and function of immune cell trafficking http://dx.doi.org/10.4161/cam.21054 tions for the control of CNS immune through the choroid plexus into the *Correspondence to: Rick B. Meeker; responses. cerebral ventricles. How are these cells Email: [email protected] recruited? What regulates the extent and selectivity of the trafficking? How do the Commentary to: Meeker RB, Bragg DC, Poulton W, Hudson L. Transmigration of macro- Once considered isolated from the immune cells function after entry into phages across the choroid plexus epithelium in immune system, it is now clear that the the CSF? In this commentary we discuss response to the feline immunodeficiency virus. central nervous system (CNS) is continu- the dynamic role of the choroid plexus Cell Tissue Res 2012; 347:443–55; PMID:22281685; ously monitored by immune cells, many of in the control of CNS immune cell http://dx.doi.org/10.1007/s00441-011-1301-8 which circulate through the cerebrospinal trafficking. 390 Cell Adhesion & Migration Volume 6 Issue 5 COMMENTARY The Choroid Plexus and Meningeal the cuboidal epithelium, which expresses shown by studies demonstrating a potent Vasculature as a Gateway tight junctions that form the blood-CSF immune response after delivery of antigens to the CNS barrier. While the epithelium serves many directly into the CSF18 and the devel- functions that have been the focus of opment of unusually high systemic viral The choroid plexus is a specialized organ excellent reviews,11,14 this commentary will titers after infusion of immunodeficiency with unique properties, the best known of discuss the role of the choroid plexus in the virus into the CSF.19 Numerous studies which is the production of CSF. It extends regulation of immune cell trafficking. have subsequently illustrated that the from the ependyma of the lateral, third and choroid plexus and meninges are uniquely fourth ventricles of the brain and is Adhesion Molecule Expression structured to support and regulate immune composed of blood vessels surrounded by in the Choroid Plexus cell trafficking. a stromal matrix and a single layer of Adhesion molecules are expressed on cuboidal epithelium (Fig. 1).2 CSF is Early studies of the choroid plexus began to the epithelium. An important feature of the produced by the cuboidal epithelium at a reveal its potential immunological import- choroid plexus is the expression of the high rate of 0.2–0.4 ml/min/g of tissue in ance by demonstrating the expression of adhesion molecules VCAM-1, ICAM-1, mammals with a turnover of 3–4 times/ adhesion molecules on the surface of the P-selectin and E-cadherin on the epithe- day.11-13 To support this production of choroid plexus epithelium and the ability lium rather than the vascular endothe- CSF, the choroid plexus maintains a rate of of the epithelial cells to present antigen to lium.7,20-24 This suggests that trafficking blood flow that is ~5–10 times greater than T cells.15 Anatomical studies described within the choroid plexus is largely con- other tissues. This high rate of blood flow macrophages on the surface of the ven- trolled by the epithelium. These adhesion and the absence of a vascular barrier tricles (epiplexus cells) suggesting that these molecules are also expressed along venules (fenestrated capillaries with no tight junc- cells may traffic into the CSF from the at the base of the choroid plexus and within tions) also provide excellent exposure to choroid plexus.16 Support for this view was the meninges.7,25 Importantly, ICAM-1, circulating immune cells within the choroid obtained from experiments showing that VCAM-1 and P-selectin are constitutively plexus. Cells that transmigrate across the systemically delivered markers that do not expressed at these sites suggesting an endothelium enter a stromal matrix that cross the blood-brain or blood-CSF barriers environment that supports continuous traf- contains numerous macrophages and dend- did appear in ventricular macrophages.17 ficking of immune cells and immunosur- ritic cells poised for interactions. To gain Highly efficient communication between veillance of the nervous system.9,10 Other access to the CSF, cells must then traverse the CSF and the immune system was adhesion molecules such as MadCAM are Figure 1. Left: schematic representation of the choroid plexus showing the multi-lobed structure that extends from the ependyma into the lateral, third and fourth ventricles. The choroidal artery and arterioles entering through the stalk provide a rich supply of blood that circulates through the choroid plexus and then exits via venules. Right: a small segment of epithelium adjacent to a single capillary is depicted. The vascular endothelium is separated from the epithelium by a stromal matrix that contains numerous macrophages and dendritic cells. Trafficking cells easily transmigrate across the fenestrated vascular endothelium, which has no barrier. To reach the cerebrospinal fluid (CSF) in the cerebral ventricles, migrating cells must traverse the stroma and the epithelium, which contains tight junctions that form the blood-CSF barrier. The resident macrophages and dendritic cells in the stroma may also transmigrate across the epithelium into the CSF. www.landesbioscience.com Cell Adhesion & Migration 391 expresseddenovoinresponsetospecific within the CSF of healthy adults (0–3 secondary lymphoid organs.25 Forty-six stimuli such as infections.26 VCAM-1, cells/mm3) with a CSF:blood ratio of percent of these T cells were also CD69+ ICAM-1 and MadCAM are all upregulated ~1:2,500 for lymphocytes and 1:2,000 vs. 4% in blood indicating recent activa- in the choroid plexus epithelium in response for monocytes.1,7 The composition of tion.1,25 Like the CD4+ T cells, CD8+ T to autoimmune responses,23 infection23,27 these cells is quite different from blood cells that penetrated into the CSF were and traumatic brain injury.28 Similar upre- indicating that the cells are highly selected mostly activated