Inflammatory Regulation of CNS Barriers After Traumatic Brain Injury: A Tale Directed by Interleukin-1

Abstract

Several barriers separate the central nervous system (CNS) from the rest of the body. These barriers are essential for regulating the movement of fluid, ions, molecules, and immune cells into and out of the brain parenchyma. Each CNS barrier is unique and highly dynamic. Endothelial cells, epithelial cells, pericytes, astrocytes, and other cellular constituents each have intricate functions that are essential to sustain the brain's health. Along with damaging neurons, a traumatic brain injury (TBI) also directly insults the CNS barrier-forming cells. Disruption to the barriers first occurs by physical damage to the cells, called the primary injury. Subsequently, during the secondary injury cascade, a further array of molecular and biochemical changes occurs at the barriers. These changes are focused on rebuilding and remodeling, as well as movement of immune cells and waste into and out of the brain. Secondary injury cascades further damage the CNS barriers. Inflammation is central to healthy remodeling of CNS barriers. However, inflammation, as a secondary pathology, also plays a role in the chronic disruption of the barriers' functions after TBI. The goal of this paper is to review the different barriers of the brain, including (1) the blood-brain barrier, (2) the blood-cerebrospinal fluid barrier, (3) the meningeal barrier, (4) the blood-retina barrier, and (5) the brain-lesion border. We then detail the changes at these barriers due to both primary and secondary injury following TBI and indicate areas open for future research and discoveries. Finally, we describe the unique function of the pro-inflammatory cytokine interleukin-1 as a central actor in the inflammatory regulation of CNS barrier function and dysfunction after a TBI.

Keywords: IL1R1; edema; glia; interleukin-1 receptor 1; neuroimmunology; neuroinflammation; neurotrauma.

Figure 1

The Blood Brain Barrier (BBB). (A) Brain endothelial cells (BEC) form the first layer of the BBB. An endothelial basement membrane then surrounds the BECs. Smooth muscle cells (SMC), pericytes, and border-associated macrophages (BAM) are in the next layer. Finally, the parenchymal basement membrane and the astrocytic end-feet create the perivascular space. Interleukin-1 receptor 1 (IL-1R1) is expressed in the venous compartment of the BECs, presumably on both the luminal and abluminal sides. (B) The junctions between endothelial cells form the major barrier component and consist of several proteins both in the intercellular space and intracellular compartments. (C) Traumatic brain injury causes several alterations at the BBB. These changes include (1) loss of junctional proteins, (2) microbleeds, (3) local and systemic increased cytokines, (4) pericyte disruption, (5) matrix metalloprotease (MMP) activation, (6) endothelial cell activation, (7) leukocyte infiltration, and (8) astrocyte retraction from the barrier. Many of these changes have been linked either directly (solid arrow) or indirectly (dashed arrow) with IL-1 signaling.

Figure 2

IL-1R1 gene expression in a naïve adult reporter mouse. (A) The IL-1R1 reporter mouse line expresses RFP via the IL-1R1 promoter (77) in discrete tissue compartments as seen using RFP immunohistochemistry. (B) IL-1R1 expression is high in blood vessels within the brain parenchyma, (C) choroid plexus, and (D) meninges. All of these areas are associated with one of the CNS barriers. (scale bar is 1mm in A, and 50 μm in B–D).

Figure 3

The blood-CSF barrier. (A) The blood-CSF barrier surrounds the choroid plexus situated within the ventricles of the brain. (B) The blood-CSF barrier’s endothelial cells are fenestrated, while the choroid plexus epithelial cells have tight junctions and adherens junctions between adjacent cells, creating a barrier. Kolmer cells interact with the choroid plexus epithelial cells on the ventricle side. Interleukin-1 receptor 1 (IL-1R1) is located on epithelial cells. (C) Traumatic brain injury causes alterations to the blood-CSF barrier, including (1) altered transporter localization and expression; (2) Kolmer cells become activated and retract their processes; (3) local and systemic increased cytokines; (4) increased water permeability and edema; (5) loss of tight junctions; (6) matrix metalloprotease (MMP) activity; and (7) increased leukocyte trafficking and activation. Many of these changes have been linked directly (solid arrow) or indirectly (dashed arrow) to IL-1 signaling.

Figure 4

The meningeal barrier. The meninges, covering the brain surface, consist of three main layers, the dura mater, the arachnoid mater, and the pia mater. The dura mater consists of the periosteal, meningeal, and dural border cell layers. The arachnoid trabeculae imparts the majority of the barrier properties. The pia mater covers the brain’s surface and connects with the astrocytic end-feet’s glial limitans. Interleukin-1 receptor 1 (IL-1R1) is located within the arachnoid and pia mater. Traumatic brain injury tears the blood vessels running through and covered by the meninges, resulting in subdural hemorrhage (SDH) and subarachnoid hemorrhage (SAH). Increased immune cell trafficking occurs through the altered meninges post-TBI. IL-1 signaling can be linked indirectly (dashed arrows) with hemorrhage and leukocyte trafficking and activation.

Figure 5

The blood-retina barrier. (A) The blood-retina barrier consists of two separate layers. The first (outer) around the choriocapillaris blood vessels, and the second (inner) around the blood vessels in the retinal ganglia cell layer. (B) The inner barrier consists of endothelial cells surrounded by pericytes, astrocytic end-feet, and specialized glial cells called Müller cells. Here, a TBI increases permeability and results in edema and increased leukocyte infiltration. Müller cells pull away from the barrier and activate to release reactive oxygen species (ROS) and cytokines. (C) The retinal pigment epithelial cells (RPE) connected via tight junctions form the outside barrier with the choriocapillaris blood vessels. Here, a TBI causes increased fluid accumulation through disrupted tight junctions resulting in edema. Most connection with IL-1 signaling is indirect (dashed arrows), while some direct (solid arrow) evidence connects IL-1 signaling with leukocyte trafficking.