Neuroimmune Axes of the Blood-Brain Barriers and Blood-Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions

Abstract

Central nervous system (CNS) barriers predominantly mediate the immune-privileged status of the brain, and are also important regulators of neuroimmune communication. It is increasingly appreciated that communication between the brain and immune system contributes to physiologic processes, adaptive responses, and disease states. In this review, we discuss the highly specialized features of brain barriers that regulate neuroimmune communication in health and disease. In section I, we discuss the concept of immune privilege, provide working definitions of brain barriers, and outline the historical work that contributed to the understanding of CNS barrier functions. In section II, we discuss the unique anatomic, cellular, and molecular characteristics of the vascular blood-brain barrier (BBB), blood-cerebrospinal fluid barrier, and tanycytic barriers that confer their functions as neuroimmune interfaces. In section III, we consider BBB-mediated neuroimmune functions and interactions categorized as five neuroimmune axes: disruption, responses to immune stimuli, uptake and transport of immunoactive substances, immune cell trafficking, and secretions of immunoactive substances. In section IV, we discuss neuroimmune functions of CNS barriers in physiologic and disease states, as well as pharmacological interventions for CNS diseases. Throughout this review, we highlight many recent advances that have contributed to the modern understanding of CNS barriers and their interface functions.

Fig. 1.

The neurovascular unit. The BBB is in contact and communicates with other cells of the CNS as well as circulating immune cells and peripheral tissues through the endocrine-like secretions of the latter. Differences occur in NVU function regionally as well as among the anatomic areas in which barrier cells are located. As an example of the latter, immune cell trafficking occurs largely at the postcapillary venule. Endothelial cells, astrocyes, pericytes, neurons, and macrophages/microglia, as well as the extracellular matrix and glycocalyx are part of the NVU. There is renewed interest in mast cell functions, and the cellulis incompertus represents cell types yet to be discovered that participate in the NVU. Not drawn to scale.

Fig. 2.

Axes 1 and 3: disruption, transport, and penetration. Major influx mechanisms are transcellular diffusion and saturable transport. Influx is countered by efflux (transcellular diffusion, saturable transport, reabsorption of CSF) and enzymatic activity at the BBB. Disruption can be by way of transcellular/transcytotic or paracellular mechanisms. Endothelial damage and hemorrhage are not depicted. The extracellular pathways are relatively inefficient routes of CNS uptake vs. saturable transport and used by substances that include albumin, immunoglobulins, erythropoietin, and soluble receptors.

Fig. 3.

Axis 2: modulation of barrier/interface function. Immunoactive (IA) substances work through four main pathways to alter BBB functions. (A) IA substances act on a peripheral cell that then releases a substance that acts on the barrier. Example: LPS acts on a peripheral cell inducing it to release nitric oxide, and the nitric oxide then acts on BECS to alter insulin transport. (B) IA acts on the BEC to induce an alteration mediated through intracellular machinery. Example: TNF alteration of Pgp function, which is mediated through a pathway involving nitric oxide and endothelin-1. (C) IA acts directly at a BEC receptor or transporter. Example: IL-1ra blocks BBB transport of IL-1β. (D) IA acts on barrier cell receptor/transporter (i) inducing barrier cell secretion that acts in autocrine fashion to affect barrier function (example: LPS induces BEC to secrete IL-6 and granulocyte-macrophage colony-stimulating factor, which mediates LPS-induced increase in HIV-1 passage across the BBB) or (ii) to induce barrier cell to communicate with another CNS cell whose release modifies barrier cell activity (example: presence of pericyte enhances LPS-induced increase in HIV-1 passage across the BBB).

Fig. 4.

Axis 4: immune cell trafficking. Immune cell passage across the BBB is a highly regulated process and can occur at the vascular BBB, chroroid plexus, or meninges. Passage can be between or across the BEC and involves steps that include capture, rolling, arrest, crawling, and diapedesis.

Fig. 5.

Axis 5: immune secretions by barrier cells. Secretions can be from either the luminal or abluminal surface (cell A). Secretions can be constitutive or induced by immune modulators (cell B). Barrier cells can receive immune modulator input from one surface (e.g., abluminal) and respond by secreting from the opposite surface (e.g., luminal), forming an axis that transmits neuroimmune communication across the BBB (cell C).

Fig. 6.

Sickness behavior. IL-1 induces the full spectrum of sickness behavior, but other inflammatory agents can directly or through IL-1 release elicit many aspects as well. IL-1 transport across the BBB of the posterior division of the septum (PDS) acts there to induce cognitive impairments. Prostaglandin E2 (PGE2) produced by stimulation of BEC COX-1 and COX-2 alters the HPA, induces fever, and results in malaise/discomfort, the latter mediated through dopaminergic and GABAergic pathways. COX-2 of non-BEC origin mediates anorexia. Depression-like symptoms are mediated through enhanced activity of indoleamine 2,3-dioxygenase (IDO), resulting in increased blood levels of kynurenine, which crosses the BBB using the large-neutral amino acid transporter (LAT-1). Kynurenine entry into brain is opposed by a brain-to-blood efflux transporter. Taste aversion is COX-2 independent; mechanisms of many other sickness behaviors are yet to be fully elucidated.

Fig. 7.

Chemobrain or CICD. The BBB is involved in mediation of chemobrain in two known ways. The efflux transporter Pgp prevents doxorubicin from entering the brain. TNF is transported across the BBB, where it acts directly to induce apoptosis as well as to induce release of additional TNF from glial cells.