JNeurosci The Journal of Neuroscience

Interfering with the Chronic Immune Response Rescues Chronic Degeneration After Traumatic Brain Injury

Ali Erturk, Susanne Mentz, Erik E. Stout, Maj Hedehus, Sara L. Dominguez, Lisa Neumaier, Franziska Krammer, Gemma Llovera, Karpagam Srinivasan, David V. Hansen, Arthur Liesz, Kimberly A. Scearce-Levie, and Morgan Sheng Contributed by Sloka S. Iyengar, PhD.

Contributed by Sloka Iyengar

Journal of Neuroscience 21 September 2016 36 (38) 9962-9975; DOI: 10.1523/JNEUROSCI.1898-15.2016

Objective: Traumatic brain injury (TBI) is the cause of considerable disability, and has been shown to contribute to conditions like epilepsy, and dementia. TBI causes changes in the brain immediately (acute), and sometime after (chronic) the initial event. The characteristics of acute changes in neurons are somewhat better understood, but the features of the neurons that survive, and whether (and how) they contribute to long-term deleterious effects is not fully known. Hence, the authors of this paper used a model of TBI called the closed-head model in mice, to study these chronic alterations. In this model, mice are anesthetized, and an injury of measured magnitude is applied to the exposed skull. This gives the opportunity to not only study what happens to the brain over time, but also what happens in areas near and far away from the injury site. The authors looked at inflammatory mediators in mice that were subjected to the closed-head model.

Results: In mice subjected to the closed-head model, abnormal inflammation was found as long as a year after the initial injury. Since the life span of mice is considerably shorter than that of humans, one year represents a long time in their lives. Abnormal inflammation was found in areas of the brain both near to, and farther away from, the site of injury. After observing these general changes in the brains of mice that were subject to TBI, the authors then studied a specific molecule called CX3CR1, which is a mediator of inflammation in the brain. Experiments in transgenic mice revealed that deletion of one allele of CX3CR1 prevents the chronic, inflammatory cascade in mice caused by TBI. This effect was more pronounced in female mice as compared to male mice.

Interpretation: The current study shows that inflammatory reactions can persist for a long time after the injury, and that they might be a critical component of neurodegeneration. The authors also discovered that a molecule called CX3CR1 might mediate these long-term effects (in female mice, at least). The authors hence propose that chronic inflammation may be a potential target to develop therapies for subjects with TBI.

Summary for specialists