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

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Neuroimmune Axes of the Blood–Brain Barriers and Blood–Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions 1521-0081/70/2/278–314$35.00 https://doi.org/10.1124/pr.117.014647 PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:278–314, April 2018 Copyright © 2018 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: ROBERT DANTZER Neuroimmune Axes of the Blood–Brain Barriers and Blood–Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions Michelle A. Erickson and William A. Banks Geriatric Research and Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington; and Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington Abstract. ....................................................................................279 I. Introduction. ..............................................................................280 A. The Blood–Brain Barrier and Immune Privilege .........................................280 B. Working Definitions of Brain Barriers and Interfaces ....................................280 C. Historical Work: Defining the Brain Barriers . ..........................................280 Downloaded from II. Features and Functions of the Blood–Brain Barrier and Blood–Brain Interface . .............281 A. Specialized Features That Confer Barrier Functions .....................................281 1. Tight Junctions ......................................................................281 2. Reduced Macropinocytosis............................................................282 3. Efflux Transporters ..................................................................282 by guest on September 27, 2021 4. Metabolic Enzymes ..................................................................282 B. Specialized Features That Confer Interface Functions....................................282 1. Transcellular Diffusion. ............................................................282 2. Blood–Brain Barrier Transport via Solute Carriers ...................................283 3. Blood–Brain Barrier Transport via Receptor-Mediated Transcytosis ...................283 4. Blood–Brain Barrier Transport via Adsorptive Transcytosis . .........................283 C. From Brain Barriers to Brain Interfaces: Components of the Neurovascular Unit . .......284 1. Endothelial Cells. ..................................................................284 2. Brain Pericytes ......................................................................284 3. Astrocytes . ........................................................................285 4. Neurons .............................................................................286 5. Microglia and Perivascular Macrophages . ..........................................286 6. Mast Cells . ........................................................................286 7. Extracellular Matrix .................................................................286 8. Glycocalyx . ........................................................................287 D. Arms of the Blood–Brain Barrier and Their Neuroimmune Functions. ...................287 1. The Vascular Blood–Brain Barrier . ................................................287 2. The Blood–Cerebrospinal Fluid Barrier...............................................287 3. Tanycytic/Ependymal Barriers of Circumventricular Organs . .........................288 III. The Neuroimmune Axes . ..................................................................289 A. Axis 1: Blood–Brain Barrier Disruption . ................................................289 1. Disruption of Paracellular Tight Junctions. ..........................................290 2. Transcytotic Vesicular Pathways .....................................................290 3. Endothelial Cell Damage and Hemorrhage . ..........................................291 B. Axis 2: Modulation of Barrier and Interface Functions by Immune Substances............291 Address correspondence to: Dr. William A. Banks, Veterans Affairs Puget Sound Health Care System, Room 810A/Building 1, 1660 S. Columbian Way, Seattle, WA 98108. E-mail: [email protected] This work was supported by the Department of Veterans Affairs and the National Institutes of Health National Institute on Aging [Grant R01 AG046619]. https://doi.org/10.1124/pr.117.014647. 278 BBB and Neuroimmune Axes 279 C. Axis 3: Transport, Penetration, and Uptake of Neuroimmune-Related Substances. .......292 D. Axis 4: Immune Cell Trafficking between Blood and Brain ...............................294 E. Axis 5: Immune Secretions of the Barrier Cells ..........................................296 IV. Physiologic Conditions, Disease States, and Pharmacologic Agents . .........................297 A. Sickness Behavior .......................................................................297 B. Perinatal Brain Ischemia ................................................................297 C. Multiple Sclerosis .......................................................................298 D. Human Immunodeficiency Virus-1 Penetration of the Blood–Brain Barrier and Consequences of Human Immunodeficiency Virus-1 Infection on Blood–Brain Barrier Function . ..............................................................................299 E. Amyloid b Peptide and Alzheimer Disease ...............................................300 F. Neuromyelitis Optica. ..................................................................301 G. Euthyroid Sick Syndrome . ............................................................301 H. Chemobrain.............................................................................301 I. Inflammation, ATP-Binding Cassette Transporters, and Central Nervous System Drug Delivery. ..............................................................................302 J. Emergence of Progressive Multifocal Leukoencephalopathy Associated with Therapies That Inhibit T-Cell Immune Surveillance ................................................303 K. IL-1ra, Febrile Infection-Related Epilepsy Syndrome, and Neonatal-Onset Multisys- tem Inflammatory Disease. ............................................................303 L. Immunomodulatory Therapies and Stroke ...............................................304 M. Methamphetamine and Blood–Brain Barrier Alterations . ...............................304 N. Cerebral Cavernous Malformations ......................................................304 O. Antibody-Associated Autoimmune Encephalitis Syndromes ...............................304 V. Conclusions and Future Directions...........................................................305 Acknowledgments . ........................................................................306 References ..................................................................................306 Abstract——Central nervous system (CNS) barriers pre- vascular blood–brain barrier (BBB), blood–cerebrospinal dominantly mediate the immune-privileged status of the fluid barrier, and tanycytic barriers that confer their brain, and are also important regulators of neuroimmune functions as neuroimmune interfaces. In section III,we communication. It is increasingly appreciated that consider BBB-mediated neuroimmune functions and communication between the brain and immune system interactions categorized as five neuroimmune axes: contributes to physiologic processes, adaptive responses, disruption, responses to immune stimuli, uptake and and disease states. In this review, we discuss the highly transport of immunoactive substances, immune cell specialized features of brain barriers that regulate trafficking, and secretions of immunoactive substances. neuroimmune communication in health and disease. In In section IV, we discuss neuroimmune functions of section I, we discuss the concept of immune privilege, CNS barriers in physiologic and disease states, as well provide working definitions of brain barriers, and outline as pharmacological interventions for CNS diseases. the historical work that contributed to the understanding of Throughout this review, we highlight many recent advances CNS barrier functions. In section II, we discuss the unique that have contributed to the modern understanding of anatomic, cellular, and molecular characteristics of the CNS barriers and their interface functions. ABBREVIATIONS: Ab, amyloid b;ABC,ATP-bindingcassette;AD,Alzheimer disease; AJ, adherens junction; ART, anti-retroviral therapy; BALT, bronchus-associated lymphoid tissue; BBB, blood–brain barrier; BCRP, breast cancer resistance protein; BCSFB, blood–CSF barrier; BEC, brain endothelial cell; BUI, brain uptake index; CCL, C-C motif chemokine ligand; CICD, chemotherapy-induced cognitive dysfunction; CMB, cerebral microbleed; CNS, central nervous system; COX, cyclooxygenase; CP, choroid plexus; CPE, choroid plexus epithelium; CSF, cerebrospinal fluid; CVO, circumventricular organ; DHA, docosahexaenoic acid; DOX, doxorubicin; EAE, experimental autoimmune encephalomyelitis; ECM, extracellular matrix; FIRES, febrile infection-related epilepsy syndrome; GRP78, glucose-regulated protein 78; HAART, highly active antiretroviral therapy; HAND, HIV- associated neurologic disorder; HIV, human immunodeficiency virus; HIVE, HIV encephalitis; IDT, indicator diffusion technique; IFN, interferon;IL, interleukin; IL-1R1, type 1 IL-1 receptor; ISF, interstitial fluid; JAM, junctional adhesion molecule; LPC, lysophosphatidylcholine; LPS, lipopolysaccharide;
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