Depression Following a Traumatic Brain Injury: Uncovering Cytokine Dysregulation as a Pathogenic Mechanism

A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury (TBI). Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life

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

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

Depression following a traumatic brain injury: uncovering cytokine dysregulation as a pathogenic mechanism

A substantial number of individuals have long-lasting adverse effects from a traumatic brain injury (TBI). Depression is one of these long-term complications that influences many aspects of life. Depression can limit the ability to return to work, and even worsen cognitive function and contribute to dementia. The mechanistic cause for the increased depression risk associated with a TBI remains to be defined. As TBI results in chronic neuroinflammation, and priming of glia to a secondary challenge, the inflammatory theory of depression provides a promising framework for investigating the cause of depression following a TBI. Increases in cytokines similar to those seen in depression in the general population are also increased following a TBI. Biomarker levels of cytokines peak within hours-to-days after the injury, yet pro-inflammatory cytokines may still be elevated above physiological levels months-to-years following TBI, which is the time frame in which post-TBI depression can persist. As tumor necrosis factor α and interleukin 1 can signal directly at the neuronal synapse, pathophysiological levels of these cytokines can detrimentally alter neuronal synaptic physiology. The purpose of this review is to outline the current evidence for the inflammatory hypothesis of depression specifically as it relates to depression following a TBI. Moreover, we will illustrate the potential synaptic mechanisms by which tumor necrosis factor α and interleukin 1 could contribute to depression. The association of inflammation with the development of depression is compelling; however, in the context of post-TBI depression, the role of inflammation is understudied. This review attempts to highlight the need to understand and treat the psychological complications of a TBI, potentially by neuroimmune modulation, as the neuropsychiatric disabilities can have a great impact on the rehabilitation from the injury, and overall quality of life

Interleukin-1 Receptor 1 signaling in mild TBI: do endothelial cells play a major role?

Across the world, over 69 million people sustain a traumatic brain injury (TBI) per year making TBI a major health concern worldwide. Of all the TBIs that occur each year, it is suggested that up to 90 percent are mild in nature. Even a mild TBI causes both physical damages to the cells of the brain and activation of a variety of biochemical cascades. Inflammation is an extremely common pathology seen in the brains of TBI survivors of all severities. Chronic inflammation can cause detrimental effects within the brain including neurodegeneration. A major pro-inflammatory cytokine, interleukin-1 (IL-1), is upregulated within hours of the physical insult and can persist through activation of several different cell types within the brain. Interluekin-1 binds mainly to IL-1 receptor 1 (IL-1R1) which is expressed on endothelial cells 10-fold more than other cell types in the brain. While historically understudied in TBI, endothelial cells present a unique target for pre-clinical studies. Endothelial cells are not only disrupted by TBI in structure and function, but they can also respond to and release inflammatory signals to participate in the post-TBI inflammatory response. We thus focused on IL-1R1 and endothelial IL-1 signaling following a mild TBI animal model. We hypothesized that following mild TBI, brain endothelial cells serve as a mediator of neuroimmune responses via IL-1R1. Our mild closed head injury (CHI) model causes an increase in IL-1R1 expression in several brain regions after injury. Further, we found that our model induced inflammatory processes within 9 hours post-CHI which had mostly recovered by 72 hours. However, in an IL-1R1 global knock-out and endothelial-only restore model, we found a shifted inflammatory profile. We believe that this suggests the importance of communication between multiple cell types for IL-1 signaling in the brain following mild TBI. Thus, future studies into post-traumatic inflammation should focus on cell communication events to attempt to reduce inflammation and improve recovery