Advances in Meningeal Immunity

Abstract

The central nervous system (CNS) is an immunologically specialized tissue protected by a blood-brain barrier. The CNS parenchyma is enveloped by a series of overlapping membranes that are collectively referred to as the meninges. The meninges provide an additional CNS barrier, harbor a diverse array of resident immune cells, and serve as a crucial interface with the periphery. Recent studies have significantly advanced our understanding of meningeal immunity, demonstrating how a complex immune landscape influences CNS functions under steady-state and inflammatory conditions. The location and activation state of meningeal immune cells can profoundly influence CNS homeostasis and contribute to neurological disorders, but these cells are also well equipped to protect the CNS from pathogens. In this review, we discuss advances in our understanding of the meningeal immune repertoire and provide insights into how this CNS barrier operates immunologically under conditions ranging from neurocognition to inflammatory diseases.

Figure 1

Steady-State Meningeal Anatomy and Immune Composition. The meninges covering the central nervous system (CNS) parenchyma consist of the dura mater (adjacent to the skull which is not shown), arachnoid mater, and pia mater. The dura mater is similar to a peripheral tissue with its lymphatic vessels and fenestrated vasculature that allow entry of large molecules (e.g., 45 kDa) from the blood. The dura mater has a large repertoire of immune sentinels, such as dendritic cells (DC), mast cells (MC), innate lymphoid cells (ILCs), meningeal macrophages, T cells, and B cells. The arachnoid mater represents the first impermeable barrier to the CNS parenchyma, as cells within this layer are joined by tight junctions. Therefore, molecules cannot diffuse freely from the dura mater into the subarachnoid space. The subarachnoid space is filled with cerebrospinal fluid, which removes cells and compounds unless they are attached to the stromal matrix (purple). The brain surface is traversed by nonfenestrated veins and arteries encased in the pial sheaths (not shown). Although not surrounded by astrocytic endfeet, vascular endothelial cells in the pia mater meninges are impermeable and joined by tight junctions. The pia matter also contains immune sentinels, although less numerous than in the dura, such as mast cells (not depicted), macrophages, and dendritic cells. The pia mater and glia limitans (formed by surface-associated astrocytes and astrocytic endfeet) represent the final barrier before the parenchyma. Diffusion of small molecules (3 kDa) is restricted to the superficial layers of the parenchyma, and larger molecules cannot cross this barrier.

Figure 2

Meningeal Innervation. The dura mater is innervated by a network of peripheral nerve fibers that project onto vascular and nonvascular targets. Upon activation, sympathetic fibers from the superior cervical ganglion release noradrenaline (NAD), which promotes vasoconstriction and restricts permeability. By contrast, parasympathetic fibers from the sphenopalatine and otic ganglion increase vascular permeability and promote vasodilation through the action of acetylcholine (ACH). Finally, branches of the trigeminal ganglion, that also innervate the pia mater (not shown), can both release neuropeptides [e.g., calcitonin gene-related peptide (CGRP), substance P, pituitary adenylate cyclase-activating polypeptide (PACAP)] through efferent fibers and sense nociceptive stimuli, such as cold, heat, pH, and mechanical forces through afferent fibers. Myelinated fibers are not shown.

Figure 3

Meningeal and Parenchymal Inflammation during EAE. Experimental autoimmune encephalitis (EAE) is triggered by autoreactive T cells that first invade the meninges. They extravasate from inflamed dural vessels and encounter infiltrating antigen-presenting cells (APCs) [e.g., macrophages and dendritic cells (DC)]. They are reactivated within immune clusters that contain innate lymphocytes (ILCs). Those ILCs reside in the meninges and foster APC-T cell interactions, as well as inflammation, by triggering cytokine and matrix metalloproteinase release (see details in the text). T cells also extravasate from pial vessels or possibly cross the arachnoid mater if it has been damaged by inflammation. In the leptomeninges, autoreactive T cells are attracted by APCs that release chemokines such as CCL5, CXCL9, CXCL10, and CXCL11. Adhesion molecules, such as intercellular adhesion molecule 1 (ICAM), are upregulated on APCs and mediate interactions with lymphocyte function-associated antigen 1 (LFA-1) on infiltrating T cells. These interactions prevent T cell detachment into the convective flow of the cerebrospinal fluid (CSF). Following reactivation by APCs, T cells likely cross the glia limitans at the surface of the brain as well as from perivascular spaces (not shown). Within the parenchyma, T cells encounter additional APCs and microglia that promote release of inflammatory molecules and chemoattractants that recruit pathogenic monocytes and neutrophils from the blood. This causes myelin and axonal damage, ultimately causing neurological dysfunction. MHC, Major histocompatibility complex; TCR, T cell receptor.

Figure 4

Physiopathology of Migraines. The brain parenchyma does not have nociceptors, and painful stimuli are generally triggered by activation of dural sensory fibers. Among nociceptive stimuli, the most commonly studied form of migraine is triggered by an intense and fast depolarizing wave in the parenchyma of unknown etiology (referred to as a cortical spreading depression or CSD). This promotes activation of fibers emanating from the trigeminal ganglion (TG) that project onto dural blood vessels. Neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P (SP), are released on blood vessels and mast cells (MC), with the latter producing serotonin (5-HT) and histamine (HIS). This causes vasodilation of dural blood vessels and directly activates efferent fibers, triggering the sensation of pain.