The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS Weller, Roy O.; Sharp, Matthew M.; Christodoulides, Myron; Carare, Roxana O.; Møllgård, Kjeld Published in: Acta Neuropathologica DOI: 10.1007/s00401-018-1809-z Publication date: 2018 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Weller, R. O., Sharp, M. M., Christodoulides, M., Carare, R. O., & Møllgård, K. (2018). The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS. Acta Neuropathologica, 135(3), 363-385. https://doi.org/10.1007/s00401-018-1809-z Download date: 28. Sep. 2021 Acta Neuropathologica (2018) 135:363–385 https://doi.org/10.1007/s00401-018-1809-z REVIEW The meninges as barriers and facilitators for the movement of fuid, cells and pathogens related to the rodent and human CNS Roy O. Weller1 · Matthew M. Sharp1 · Myron Christodoulides2 · Roxana O. Carare1 · Kjeld Møllgård3 Received: 5 November 2017 / Revised: 2 January 2018 / Accepted: 15 January 2018 / Published online: 24 January 2018 © The Author(s) 2018. This article is an open access publication Abstract Meninges that surround the CNS consist of an outer fbrous sheet of dura mater (pachymeninx) that is also the inner peri- osteum of the skull. Underlying the dura are the arachnoid and pia mater (leptomeninges) that form the boundaries of the subarachnoid space. In this review we (1) examine the development of leptomeninges and their role as barriers and facilita- tors in the foetal CNS. There are two separate CSF systems during early foetal life, inner CSF in the ventricles and outer CSF in the subarachnoid space. As the foramina of Magendi and Luschka develop, one continuous CSF system evolves. Due to the lack of arachnoid granulations during foetal life, it is most likely that CSF is eliminated by lymphatic drainage pathways passing through the cribriform plate and nasal submucosa. (2) We then review the fne structure of the adult human and rodent leptomeninges to establish their roles as barriers and facilitators for the movement of fuid, cells and pathogens. Leptomeningeal cells line CSF spaces, including arachnoid granulations and lymphatic drainage pathways, and separate elements of extracellular matrix from the CSF. The leptomeningeal lining facilitates the trafc of infammatory cells within CSF but also allows attachment of bacteria such as Neisseria meningitidis and of tumour cells as CSF metastases. Single layers of leptomeningeal cells extend into the brain closely associated with the walls of arteries so that there are no perivas- cular spaces around arteries in the cerebral cortex. Perivascular spaces surrounding arteries in the white matter and basal ganglia relate to their two encompassing layers of leptomeninges. (3) Finally we examine the roles of ligands expressed by leptomeningeal cells for the attachment of infammatory cells, bacteria and tumour cells as understanding these roles may aid the design of therapeutic strategies to manage developmental, autoimmune, infectious and neoplastic diseases relating to the CSF, the leptomeninges and the associated CNS. Keywords Leptomeninges · CSF · Barriers and facilitators · Developing human and rat brain · Perivascular compartments and spaces · Attachment of Neisseria meningitidis, infammatory cells and tumour cells to leptomeninges · Lymphatic drainage of the CNS Introduction The meninges covering the rodent and human CNS are * Roy O. Weller [email protected] divided primarily into the dura mater or pachymeninx and the arachnoid and pia mater or leptomeninges. Both dura 1 Clinical Neurosciences, South Academic Block, Level and arachnoid encompass the brain and spinal cord and the D, LD66, MP806, Faculty of Medicine University arachnoid forms the outer barrier that contains CSF within of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK the subarachnoid space (SAS). The pia is more closely applied to the brain and spinal cord but is separated from 2 Neisseria Research Laboratory, Molecular Microbiology, MP814, Academic Unit of Clinical and Experimental the CNS tissue on the surface of the CNS by a subpial space Sciences, Sir Henry Wellcome Laboratories, University containing blood vessels and varying amounts of collagen. of Southampton Faculty of Medicine, Southampton General For decades the meninges had been considered to be no Hospital, Southampton SO16 6YD, UK more than a protective shield, but recent evidence suggests 3 Department of Cellular and Molecular Medicine, Faculty that leptomeninges have complex functions as barriers and of Health and Medical Sciences, University of Copenhagen, facilitators for the movement of fuid, solutes and cells at Blegdamsvej 3, 2200 Copenhagen, Denmark Vol.:(0123456789)1 3 364 Acta Neuropathologica (2018) 135:363–385 the surface of the CNS and of fuid and solutes within the experimental studies examining the relationships between CNS parenchyma. Thus, the SAS functions as an important infammatory cells and leptomeninges are performed in distribution system. The fundamental pattern of blood sup- mice and how these studies relate directly to the human ply to the CNS is diferent from that of most other organs in leptomeninges needs to be clearly defned. Although many which a single artery and accompanying veins penetrate the investigations of the leptomeninges are performed through surface at a single point and divide into smaller and smaller the medium of immunocytochemistry, ultrastructural stud- branches within the organ. In the CNS, the arteries branch ies form a valuable contribution to our understanding of and divide into small muscular arteries and arterioles within the exact relationships between the delicate cell layers the SAS prior to entering the brain and spinal cord, the sur- of leptomeninges and other structures within the human face of which is covered by a close network of numerous CNS. For this reason, we illustrate the structure of the small vessels that enter and leave the CNS. The outer barri- adult human leptomeninges largely by their ultrastructure. ers of the brain function as morphogenetic signalling centres Barrier functions of the leptomeninges constitute an [27, 89], dynamic transport systems [108], a stem cell niche emerging feld of research in both human and rodent CNS [27] and regulators of immune cell entry into the CNS [93] and are discussed in this review. However, just as impor- as summarised by Brøchner et al. [14]. tant to the biology and pathology of the CNS is the role The adult CNS is separated from peripheral tissues by a of leptomeninges as facilitators for the movement of fuid, set of structures and physiological mechanisms that are pre- solutes and infammatory cells in relation to the CNS and sent at various interfaces between the CNS parenchyma and it diseases. Leptomeninges as facilitators for attachment surrounding fuids. Five main interfaces can be identifed in and movement of cells are also important in infections the adult brain: (a) the arachnoid barrier, (b) the blood–brain and tumour metastases in the SAS. We will review the barrier, (c) the blood–CSF barrier, (d) circumventricular attachment of bacteria to leptomeningeal cells, especially organs (CVO) barrier formed by tight junctions between with regard to Neisseria meningitidis, and the role that adjacent tanycytes, (e) the inner interface between the CSF leptomeningeal elements may play in the location and and the brain (glia limitans) in the adult. An additional sixth spread of tumour metastases within the SAS. Although in interface, (f) the interface between the CSF and the embry- its early stages, the identifcation of ligands on the surfaces onic brain is present only in the foetus [62, 83]. In the adult, of leptomeningeal cells to which bacteria and tumour cells an arachnoid blood–CSF barrier separates the fenestrated attach has clear implications for therapies in these and blood vessels in the dura from the CSF in the SAS by means other disorders involving the leptomeninges. of a cell layer joined by tight junctions (the arachnoid bar- As often occurs in felds undergoing active investi- rier layer) [65]. Since the arachnoid blood–CSF barrier is gation, misconceptions have arisen and are perpetuated avascular and provides a relatively small surface area, it is within the literature in relation to the leptomeninges and generally considered that it does not contribute signifcantly to the exchange and drainage of fuid associated with the to blood–brain exchange [1]. However in light of recent fnd- CNS. For example, it has been assumed, perhaps wrongly, ings of drug transporters and drug-metabolising enzymes that the SAS is lined by collagen, that there are perivascu- in the arachnoid blood–CSF barrier [108] and taking into lar spaces for the entry of CSF into the brain and for the account that the arachnoid barrier cell layer constitutes a drainage of interstitial fuid (ISF) from the brain. Further- much larger fraction of the brain surface area during early more, the concept of the CSF as a sink for the drainage development, it is clear that the arachnoid blood–CSF bar- of ISF from the brain may need to be re-examined, par- rier is an important and changing interface that should not ticularly as the best estimate is that 85% of ISF from the be ignored. It clearly warrants further investigation in the brain drains to lymph nodes and only 15% of ISF passes developing and adult brain. into the CSF under normal conditions [94]. These experi- In this review, we frst examine the involvement of the ments were performed in the rat using radioiodinated leptomeninges in the development of the human and rat serum albumin. Injections into the caudate nucleus and brains. We then review the structure of the adult leptome- internal capsule resulted in 10–15% of tracer passing into ninges to establish the interrelations between leptomenin- CSF. Injections into the much smaller midbrain resulted ges, CSF, blood vessels and the CNS parenchyma.