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.

Traumatic Brain Injury Induced Microglial and Caspase3 Activation in the Retina

“…Based on our results, microglial activation clearly occurred in both the sTBI and rmTBI models. This suggests that the assumption from previous research about only 40% of TBI patients having a negative retinal impact appears to be highly underestimated [12]. Surprisingly, although we observed a high level of activation at sTBI, the data measured in rmTBI was not far behind those measured in sTBI, which may be alarming in cases where someone (e.g., sports such as football, boxing) is continuously exposed to minor cranial injuries [29].…”

“…1; [11]). TBI also includes retinal injury, which, according to current data, occurs in 20-40% of affected millions in TBI [12]. Mapping these lesions and also milder effects on the retina may help to understand the pathophysiology of TBI and may be an indicative factor in screening for severe cases.…”

Intranasal Salvinorin A Improves Long-term Neurological Function via Immunomodulation in a Mouse Ischemic Stroke Model

“…Circulating neutrophils are the main infiltrating peripheral immune cells within one hour and peaking by 24 h post-injury (Gelderblom et al 2009 ). Previous studies demonstrated that neutrophil depletion reduced BBB leakiness after brain injury (Bodnar et al 2021 ; Wei et al 2021 ). Conversely, the increased permeability of BBB facilitates neutrophil infiltration into the brain after ischemic stroke (Obermeier et al 2013 ).…”

“…Circulating neutrophils are the main infiltrating peripheral immune cells within one hour and peaking by 24 h post-injury (Gelderblom et al 2009). Previous studies demonstrated that neutrophil depletion reduced BBB leakiness after brain injury (Bodnar et al 2021;Wei et al 2021).Conversely, the increased permeability of BBB facilitates neutrophil infiltration into the brain after ischemic stroke (Obermeier et al 2013).In this study, SA treatment significantly decreased the neutrophil/macrophage infiltration into the brain tissue while not altering the peripheral immune cells, suggesting that SA may play an immunomodulatory role though preserving BBB integrity. The cadaverine leakage density and plasma IgG leakage detection further demonstrated the beneficial effect of SA on the BBB.…”

Cross-Talk and Subset Control of Microglia and Associated Myeloid Cells in Neurological Disorders

“…Briefly, pvBAMs may contribute to vascular inflammation, blood–brain barrier (BBB) permeability, nutrient exchange, and metabolism, as well as HPA axis regulation [ 70 , 71 ]. Given that the choroid plexus interfaces between the periphery and CNS, immune cell activation in this compartment may aid in T-cell trafficking and antigen presentation in the meninges [ 67 , 68 , 72 ], along with neutrophil invasion [ 69 , 73 ]. With an opportune location, cpMɸ are crucial in the development of neurological sequalae of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), and TBI.…”