It’s the final quarter of the football game. The wide receiver is headed towards the goal line, football tucked under his arm, and the opposing team’s linebacker is hot on his trail. The crowd watches nervously as the linebacker closes the gap to the wide receiver and tackles him to the ground. The scene plays in slow motion as the wide receiver’s head collides with the turf, leaving the player lying on the ground, disoriented and nauseous. Like so many other football players before, he has just received a concussion—a form of traumatic brain injury (TBI). Unfortunately for both athletes and non-athletes, TBIs are not uncommon occurrences.
A traumatic brain injury is defined as a disruption in the normal brain function caused by an outside force, usually a blow to the head [1]. All TBIs can be broken down into two events: the primary injury and the secondary injury [2]. The primary injury refers to the direct biological impact caused by the initial trauma, which encompasses anything from concussions to tears in the brain tissue [2]. This event then leads to the secondary injury, which is an indirect result of TBIs and has more long-lasting effects on the patient. Secondary injuries are damages sustained by the body’s response to the primary injury. They are the result of the body’s inability to properly cope with the damage done by the primary injury and can occur in the hours or days following the initial trauma. They include a myriad of conditions, such as neuroinflammation and cell death [2]. For patients like the wide receiver in the above scenario, the resulting secondary injuries can be detrimental to their prognosis. In fact, it has been theorized that the secondary injury may be more harmful than the primary injury due to its long-lasting effects.
Epidemiologically, TBIs are some of the most common and complicated injuries in the world. They account for the greatest number of deaths and disabilities among all trauma-related injuries [3], with 1.7 million new TBIs every year in the U.S. and 5.3 million Americans currently living with TBI-related disabilities [4]. For comparison, about 805,000 Americans have a heart attack each year [5], making TBIs about twice as common as heart attacks in the U.S. Neurologically, the lasting effects of TBIs due to secondary injuries, such as learning and memory deficits caused by neuroinflammation, make them one of the most complicated injuries. One-half of all patients report three or more persistent complications, such as impaired motor and memory skills, a year after the primary injury [4]. The effect of TBIs on the body are so diverse and difficult to generalize due to varying structural brain damage patterns, and as a result, there is no standard treatment for these injuries despite their frequency [6].
Currently, treatment plans mostly remain specific to individual injuries, but often include rest and in severe cases, surgery [7]. However, these treatments are limited to addressing symptoms as they appear rather than preventing the onset of further symptoms. Because the latter option serves to mitigate the effects of the TBI, it is likely to reduce the patient’s suffering more than attempting to fix existing damage would. These limitations account for the large proportion of TBI patients who suffer from lasting effects of their injury. However, new insights into how neuroinflammation—one of the most common secondary injuries—shifts from beneficial to harmful and the role that specific types of cells such as microglia play in causing neuroinflammation can help researchers uncover new and more effective methods of treating TBIs.
Neuroinflammation is characterized by swelling and other inflammatory processes in nervous tissue, which is found in the brain, spinal cord, and associated nerves [4]. It is a necessary part of recovery after TBIs, as it is part of the body’s natural immune response. Nonetheless, neuroinflammation can also have negative side effects that delay patient recovery, such as impaired learning, if it persists longer than necessary. The shift from “good” to “bad” neuroinflammation is highly dependent on the activity of cells in the central nervous system (CNS) called microglia. Microglia assert a neuroprotective role against native and invasive pathogens. These cells are found in both the brain and spinal cord and account for five to ten percent of all cells found in the CNS [6]. Similar to the defensive line in football, microglia are the first line of defense in the brain; hence, their role in the brain’s immune response to a TBI is significant. As the primary form of active immune defense in the CNS, microglia show higher levels of activity around the site of injury and cause neuroinflammation by activating certain genes that cause swelling [2]. Microglia have become an area of interest for researchers looking to learn more about TBIs.
Due to their role in neuroinflammation, microglia also cause the swelling to shift from beneficial to harmful. Initially, microglia play a major role in the beneficial aspects of neuroinflammation by promoting the formation of new neurons, the regeneration of the part of the neuron through which signals are sent, and the creation of the insulating layer around nerves to increase their efficiency [8]. These are all key factors in repairing damaged brain tissue after a TBI. Additionally, microglia can release molecules called neurotrophic factors that promote the growth, survival, and differentiation—or specialization—of neurons, which is pertinent to recovery of the brain tissue. They also foster regeneration and the clearance of damaged and dead cells, called debris, around the site of injury; this might be imagined as the clearance of debris from a collapsed building [4]. However, microglia can also cause neuroinflammation to be extremely harmful, as the persistence of activated microglia can cause irreversible neuronal death and progressive neurodegeneration [4]. As neuroinflammation can be both beneficial and harmful to patients in recovery, it is a key focus in research, as scientists determine whether it can be targeted for treatments of TBIs.
To help pinpoint the shift from beneficial to harmful neuroinflammation and better understand how the persistence of activated microglia at the site of injury can lead to negative long-term effects, researchers at the Harvard Medical School examined gene expression in microglia at three different post-injury stages [9]. The acute stage entails the first three days after injury, while the subacute stage denotes a period of time anywhere from the fourth day to three weeks post injury. Lastly, the chronic stage occurs three weeks to months or even years post injury. In their report, the researchers include an analysis of the expression of genes involved in neuroinflammation at each recovery stage in order to indicate the occurrence of neuroinflammation. Pro-inflammatory genes promote the inflammatory response, while anti-inflammatory genes stop inflammation [9].
At two days post-injury (dpi), genes associated with signalling involved in the immune response and the movement of cells are significantly upregulated, meaning their expression is increased, which suggests increased microglia activity around the injured area of the brain. At this time, the upregulation of certain pro-inflammatory genes and the downregulation, or decreased expression, of other pro-inflammatory genes creates a varied inflammatory state, meaning inflammation is not yet a predominant characteristic at the site of injury [9].
Gene analysis continued to show the beneficial aspects of neuroinflammation well into the subacute stage. At 14 dpi, both pro-inflammatory and anti-inflammatory genes, while still downregulated, showed increased expression compared to at two dpi. In addition, microglia showed an increased presence in parts of the immune system that promote inflammation and the clearing of debris via cells engulfing the particles, a process called phagocytosis. At this time, the benefits of neuroinflammation are in full swing, as gene analysis showed microglia were promoting regeneration of neurons [9]. These findings suggest that neuroinflammation promoted by microglia remains beneficial to recovery during the subacute stage, from four days to three weeks post-injury, since it contributes to tissue repair and cellular clean-up.
However, at 60 dpi, during the chronic stage of recovery, research begins to show evidence of the harmful side of neuroinflammation. In this stage, pro-inflammatory genes are upregulated, demonstrating persistent neuroinflammation at the site of injury. Another key molecular protein, the hypoxia inducible transcription factor-1α (HIF-1α), is significantly downregulated in microglia [9]. Due to the protein’s role in cell death and disrupting the blood-brain barrier, the barrier between neural blood vessels and the brain, the inhibition of HIF-1α has been connected to increased motor deficits, hypothermia, and increased lesion size in a study performed at the Hebrew University of Jerusalem [10]. Thus, a stark contrast is observed between the effects of microglia in neuroinflammation at 14 dpi and at 60 dpi. According to the results of this study, the transition between beneficial and harmful neuroinflammation occurs sometime between the subacute and chronic stages of injury recovery—or between 14 dpi and 60 dpi—when HIF-1α begins to be downregulated.
This provides insight into how researchers can target microglia to stop neuroinflammation, as well as how they might find a balance between allowing microglia to perform their natural immune response functions and preventing persistent activation of microglia. While previous attempts to broadly target immune activation in TBIs have been unsuccessful due to the exact mechanisms behind the body’s immune response remaining poorly understood, emerging research such as the study described above has aided researchers in proposing guided treatments for TBIs featuring higher specificity. This will likely improve recovery rates and prognoses for TBI patients. Certain receptors in microglia that are responsible for the movement of cells, such as the C-C chemokine receptor type 5 (CCR5), can be downregulated in order to prevent microglia from migrating to the site of injury when they are no longer useful [9]. Several studies have been successful in reducing microglia activation around injured brain regions.
One study performed by researchers at the UCLA School of Medicine demonstrated that knocking down CCR5 improved cognitive recovery in preclinical closed-head TBIs [11]. In order to discover the role of CCR5 in TBI recovery, the researchers partially deactivated, or knocked down, the gene. Gene knockdown is a loss-of-function approach researchers often use to study the function of specific genes, as researchers can infer a gene’s function by tracking how decreased expression affects the cell or organism as a whole. In this experiment, mice with TBIs performed object-recognition tasks and maze tests before and after CCR5 knockdown (kd). Those with CCR5 kd spent more time examining new objects as opposed to familiar objects and took less time to find the end of the maze with fewer errors than those without CCR5 kd [11]. Thus, knocking down the CCR5 gene has been shown to promote recovery in animals who have suffered from TBIs. As one of the first studies with a biological approach to improving cognitive recovery, this research provides a promising approach to treating TBIs more effectively.
For patients such as the football player who received a TBI after he was tackled, this research could be the difference between living with a lifelong disability and returning to their life prior to their injury. Now, let’s check back in on the football player. He is sitting in his doctor’s office as his doctor explains that the severity of his concussion caused persistent swelling in his brain called neuroinflammation and that he will likely suffer memory deficits and possibly other long-term effects. Unfortunately, his doctor has to deliver the news that there are no current treatments to prevent the harmful side-effects of neuroinflammation but that there is research being performed to develop treatments that target neuroinflammation. While this new information cannot help those who have already suffered TBIs, it can be used to develop treatments for future victims of TBIs.
New and more effective treatments for TBIs may be key to improving the prognoses of patients, whether they are football players or car crash victims, as well as reducing the number of TBI patients suffering from long-lasting disabilities. This research is necessary to ensure the best recovery possible for each patient. While further research needs to be performed to garner a more detailed understanding on when exactly microglia cause neuroinflammation to shift from beneficial to harmful, these findings provide an exciting outlook on the future of TBI treatments and for anyone who may suffer a TBI in the future.
Centers for Disease Control and Prevention. (2020, August 28). Traumatic Brain Injury & Concussion – Homepage. https://www.cdc.gov/traumaticbraininjury/index.html
Wofford K. L., Loane D. J., Cullen D. K. (2019). Acute drivers of neuroinflammation in traumatic brain injury. Neural Regeneration Research, 14(9), 1481-1489. https://doi.org/10.4103/1673-5374.255958
Dewan, M. C., Rattani, A., Gupta, S., Baticulon, R. E., Hung, Y., Punchak, M., Agrawal, A., Adeleye, A. O., Shrime, M. G., Rubiano, A. M., Rosenfeld, J. V., & Park, K. B. (2019). Estimating the global incidence of traumatic brain injury. Journal of Neurosurgery, 130(4), 1080-1097. https://doi.org/10.3171/2017.10.JNS17352
Simon, D. W., McGeachy, M. J., Bayır, H., Clark, R. S., Loane, D. J., & Kochanek, P. M. (2017). The far-reaching scope of neuroinflammation after traumatic brain injury. Nature reviews. Neurology, 13(3), 171–191. https://doi.org/10.1038/nrneurol.2017.13
Centers for Disease Control and Prevention. (2020, September 8). Heart Disease Facts. https://www.cdc.gov/heartdisease/facts.htm
Shields, D. C., Haque, A., & Banik, N. L. (2020). Neuroinflammatory responses of microglia in central nervous system trauma. Journal of Cerebral Blood Flow & Metabolism, 40(1) S25-S33. https://doi.org/10.1177/0271678X20965786
Eunice Kennedy Shriver National Institute of Child Health and Human Development. (2020, November 24). What are the treatments for traumatic brain injury (TBI)? https://www.nichd.nih.gov/health/topics/tbi/conditioninfo/treatment
Yong, H. Y. F., Rawji, K. S., Ghorbani, S., Xue, M., & Yong, V. W. (2019). The benefits of neuroinflammation for the repair of the injured central nervous system. Cellular & Molecular Immunology, 16, 540-546. https://doi.org/10.1038/s41423-019-0223-3
Izzy, S., Liu, Q., Fang, Z., Lule, S., Wu, L., Chung, J. Y., Sarro-Schwartz, A., Brown-Whalen, A., Perner, C., Hickman, S. E., Kaplan, D. L., Patsopoulous, N. A., El Khoury, J., & Whalen, M. (2019). Time-dependent changes in microglia transcriptional networks following traumatic brain injury. Front. Cell. Neurosci, 13. https://doi.org/10.3389/fncel.2019.00307
Umschweif, G., Alexandrovich, A. G., Trembovler, V., Horowitz, M., & Shohami, E. (2013). Hypoxia-inducible factor 1 is essential for spontaneous recovery from traumatic brain injury and is a key mediator of heat acclimation induced neuroprotection. Journal of Cerebral Blood Flow & Metabolism, 33(4), 524-531. https://doi.org/10.1038/jcbfm.2012.193
Joy, M. T., Assayag, E. B., Shabashov-Stone, D., Liraz-Zaltsman, S., Mazzitelli, J., Arenas, M., Abduljawad, N., Kliper, E., Korczyn, A. D., Thareja, N. S., Kesner, E. L., Zhou, M., Huang, S., Silva, T. K., Katz, N., Bornstein, N. M., Silva, A. J., Shohami, E., & Carmichael, S. T. (2019). CCR5 is a therapeutic target for recovery after stroke and traumatic brain injury. Cell, 176(5), 1143-1157. https://doi.org/10.1016/j.cell.2019.01.044