Every year, there are over 50 million cases of traumatic brain injury worldwide, making it one of the major causes of death and disability [1]. A traumatic brain injury, or TBI, has two important parts: the primary injury, which happens right as the blow or force to the head occurs, and the secondary injury, which occurs due to the effects of the primary injury and can take place between hours or days after the initial injury depending on its severity [2]. An example of a secondary injury cascade is the neuroinflammatory response, such as microglia activation. [2]. Microglia are a type of macrophage or immune cell and are important in maintaining homeostasis in the central nervous system, as well as being responsible for clearing debris and damaged cells, repairing tissue, synaptic pruning [1]. When microglia are overly activated, they can initiate inflammatory reactions that cause neuronal damage [2] [1]. TREM1, one of the regulators of inflammation, is a triggering receptor expressed on myeloid cells, a family of immune cells originating in the bone marrow that are one of the first to respond to infection. Engagement of TREM1 leads to inflammatory effects, which increase the severity of the secondary injury [3]. In a recent study, a group of Chinese researchers investigated the effects of TREM1 after traumatic brain injury to further understand its role in regulating inflammation.

To test the hypothesis that after a TBI, TREM1 was activated, researchers used a rat model to simulate brain injury. Tthe rats in the experimental group were anesthetized and a TBI was induced by using a 40-gram metal rod. The rats were then sutured and moved to recover. The control group of rats had a craniotomy performed without inflicted brain injury. TREM1 expression was measured at different time points following the injury. The rats were grouped into the control group, 6, 12, 24, 48, 72 hours, and seven days post-injury. After these time points, brain tissue from the rats was collected and analyzed using 1) western blotting analysis to measure TREM1 protein levels and 2) immunofluorescence to detect the distribution of TREM1 [4]. 

Figure: A and B show the results from the western blotting analysis, and C shows the immunofluorescence results. In A, the bands show the protein expression of TREM1 and tubulin, which is used as a control test, and in B, the graph shows TREM1 levels at different time points. In C, the immunofluorescence staining of the rats in the experimental and control groups 24 hours after the injury is shown. The anti TREM1 antibody is stained red, anti-TMEM119, -NeuN, and -GFAP antibodies are stained green, and DAPI is stained blue [1]. Researchers looked at the colocalization of the different channels to show overlap between TREM1 and TMEM119, but not NeuN and GFAP.

The western blotting analysis showed that as the number of hours post-injury increased, so did the levels of the TREM1 protein, which peaked between 24-72 hours [4]. NeuN, a neuronal marker; GFAP, an astrocytic marker; and Tmem119 were used to visualize expression levels of TREM1 via immunofluorescence. Tmem119 is a resident microglia marker, so TREM1-positive cells that are co-labeled with Tmem119 but not NeuN or GFAP suggest a high level of microglial TREM1 expression after TBI [4].

While TREM1’s role in TBI is still not fully known, the results showed that the protein levels of TREM1 were at a maximum two to three days post-injury, that they were significantly higher than the control group, and that TREM1 levels were higher in microglia [4]. This temporal and cell-specific increase implies a potential role for the TREM1 receptor in microglial-mediated inflammatory responses to TBI. Understanding the dynamics of TREM1 expression in microglia can provide valuable insights into its contribution to neuroinflammation and potentially reveal new therapeutic targets for mitigating TBI-associated damage. One of the limitations of this study was that only the early stages of TBI were focused on and that it would be beneficial to study some of the more long-term effects of TREM1 during TBI [4]. One of the risk factors for neurodegenerative disease is the inflammatory reactions caused by TBI that lead to secondary brain injury [4]. Overall, understanding the mechanism behind these reactions can help prevent neuronal damage that occurs after the injury and decrease the risk of developing neurodegenerative disease later in life as a result of TBI. 

References:

[1] Li, Y., Ren, X., Zhang, L., Wang, Y., & Chen, T. (2022). Microglial polarization in TBI: Signaling pathways and influencing pharmaceuticals. Frontiers in Aging Neuroscience, 14. https://doi.org/10.3389/fnagi.2022.901117

[2] Bagri, K., Kumar, P., & Deshmukh, R. (2021). Neurobiology of traumatic brain injury. Brain Injury, 1–8. https://doi.org/10.1080/02699052.2021.1972152

[3] Arts, R. J. W., Joosten, L. A. B., van der Meer, J. W. M., & Netea, M. G. (2012). TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors. Journal of Leukocyte Biology, 93(2), 209–215. https://doi.org/10.1189/jlb.0312145

[4] Zhang, C., Jiang, F., Liu, S., Ni, H., Feng, Z., Huang, M., Lu, Y., Qian, Y., Shao, J., & Rui, Q. (2024). TREM1 promotes neuroinflammation after traumatic brain injury in rats: Possible involvement of ERK/cPLA2 signalling pathway. Neuroscience, 561, 74–86. https://doi.org/10.1016/j.neuroscience.2024.09.036