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

Abstract

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.

Keywords: N-methyl-D-aspartic acid; astrocytes; chronic traumatic encephalopathy; concussion; inflammation; interleukin 1; major-depressive disorder; microglia; synaptic physiology; tumor necrosis factor α.

Figure 1

The effect of traumatic brain injury (TBI) on acute cytokine response, and chronic cytokine dysregulation. (a) A TBI causes local reactive microglia/macrophages and astrocytes (b). Humoral, cellular, and neural routes (c) lead to increase in local and systemic cytokines. The profile of the different cytokines (for example, interleukin (IL)-1, IL-6, and tumor necrosis factor α (TNFα)), indicated by the blue, orange, and green dots, have slightly different temporal patterns and max amplitude, but in general, follow a similar profile. (d) The acute inflammatory response to injury results in a surge of cytokines within the first hours-to-days after injury, which can be easily detected by biomarker assays (pink box). After the first week post-injury (e), cytokines fall below the level of sensitivity for most biomarker assays, but potentially remain above physiological levels (green box). Compounding factors, such as psychosocial stress and infection, may result in secondary spikes in inflammatory cytokines as measured in biomarker assays (f). Regardless, of the ability to measure cytokines in biomarker assays, therapeutically targeting the chronic dysregulated cytokines during the months-to-years after injury (g), could reduce cognitive, psychological, and physical complications of a TBI. Future studies are warranted to test this prediction. However, as cytokines have essential physiological functions, it will be necessary to have selective therapeutics that restore the physiological balance of cytokines, and not pan-immune suppression.

Figure 2

Mechanisms by which interleukin 1 (IL-1) and tumor necrosis factor (TNF) can directly regulate neuronal synaptic function. (a) (A) IL-1 and TNFα regulate the excitatory and inhibitory neurotransmitter balance. Hyperphysiological levels of cytokines, such as following a traumatic brain injury (TBI), increase excitatory (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMAPR) and N-methyl-D-aspartic acid receptor (NMDAR)) neurotransmission, while decreasing inhibitory (γ-aminobutyric acid (GABA) A receptor (GABA_AR)) neurotransmission. Cytokines can also affect the release of glutamate (Glu) from neurons, and the uptake and release of glutamate from astrocytes. (B) IL-1 and TNFα also increase the activity of the serotonin transporter (SERT), leading to a decrease in serotonin (5-HT) at the synapse. (C) Members of the IL-1 family of proteins are also involved in synapse formation and stabilization, and IL-1 signaling can regulate this process. EAAT2: Excitatory amino acid transporter 2; IL-1R1: IL-1 receptor 1; IL-1RAPL1: IL-1-receptor accessory protein like 1; IL-1RAcP: IL-1 receptor accessory protein; TNFR1: TNF receptor 1; JNK: c-Jun terminal kinase; system X_C ^-: cystine/glutamate antiporter system.