Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease

Abstract

The meninges are the fibrous covering of the central nervous system (CNS) which contain vastly heterogeneous cell types within its three layers (dura, arachnoid, and pia). The dural compartment of the meninges, closest to the skull, is predominantly composed of fibroblasts, but also includes fenestrated blood vasculature, an elaborate lymphatic system, as well as immune cells which are distinct from the CNS. Segregating the outer and inner meningeal compartments is the epithelial-like arachnoid barrier cells, connected by tight and adherens junctions, which regulate the movement of pathogens, molecules, and cells into and out of the cerebral spinal fluid (CSF) and brain parenchyma. Most proximate to the brain is the collagen and basement membrane-rich pia matter that abuts the glial limitans and has recently be shown to have regional heterogeneity within the developing mouse brain. While the meninges were historically seen as a purely structural support for the CNS and protection from trauma, the emerging view of the meninges is as an essential interface between the CNS and the periphery, critical to brain development, required for brain homeostasis, and involved in a variety of diseases. In this review, we will summarize what is known regarding the development, specification, and maturation of the meninges during homeostatic conditions and discuss the rapidly emerging evidence that specific meningeal cell compartments play differential and important roles in the pathophysiology of a myriad of diseases including: multiple sclerosis, dementia, stroke, viral/bacterial meningitis, traumatic brain injury, and cancer. We will conclude with a list of major questions and mechanisms that remain unknown, the study of which represent new, future directions for the field of meninges biology.

Innate Lymphoid Cells in the Central Nervous System

“…Brain barriers prevent the migration of ILC into brain parenchyma at steadystate. It has been shown that neurological diseases cause break down of BBB and meningeal integrity (133)(134)(135). The permeability of the BBB is notably increased in stroke and glioma during which the vasculature bed is completely remodeled and re-constructed (136,137).…”

The gut–meningeal immune axis: Priming brain defense against the most likely invaders

“…1 ). Unlike the vascular network of the CNS, which is sealed by endothelial cell tight junctions, the dural vascular bed is fenestrated ( Derk et al, 2021 ). Consistent with this, intravenous horseradish peroxidase (44 kD) accumulated throughout the dura, but not the cerebral parenchyma, in rodents and monkeys ( Balin et al, 1986 ).…”

‘Formation and function of the meninges arachnoid barrier around the developing brain’

“…The meningeal arachnoid barrier is a component of the blood-cerebrospinal fluid barrier (B-CSFB), that along with barriers at the pial vasculature and choroid plexus, regulates the free movement of molecules and cells into and out of the CSF in the subarachnoid space and ventricles (Balin et al, 1986; Ichikawa and Itoh, 2011; Ichikawa et al, 2010; Rodriguez-Peralta, 1957; Roth et al, 2013). A mechanistic understanding of how the blood-brain barrier (BBB) and B-CSFB develop and function is important, as their disruptions contribute to the pathophysiology of brain injury, neurodegenerative disorders, neuroinflammatory diseases, cancer, and the aged brain (Alves de Lima et al, 2020; Brkic et al, 2015; Derk et al, 2021; Iliff et al, 2012; Liebner et al, 2018; Sweeney et al, 2019). The arachnoid barrier separates the fenestrated blood vessels of the dura from the immune privileged CSF and is composed of epithelial-like cells connected by tight and adherens junctions (Nabeshima et al, 1975; Polanco et al, 2021; Rascher and Wolburg, 1997; Uchida et al, 2019).…”