Chronic Activation of M1-like Microglia After Single Traumatic Brain Injury in Mice
Introduction. Traumatic Brain Injury (TBI) is characterized as any external force to the head followed by altered brain function.1 TBI may occur from many different causes and can vary according to gender, age, race, and geographic location.1 Long-term effects of repetitive TBI have been linked to later development of neurodegenerative diseases, including Alzheimer’s Disease (AD), Chronic Traumatic Encephalopathy (CTE), as well as cognitive and mood dysfunction.1 Recently, it has been discovered that much like the macrophage, microglia polarize into two different subsets with different functions after TBI. M1-like microglia are considered “pro-inflammatory” and release cytokines that promote inflammation, such as IL-6.2 They are involved in the necessary process of clearing debris and dead cells from the injury site.2 M2-like microglia are “anti-inflammatory” and release cytokines that promote healing.2 New research suggests M1-like microglia can become dysregulated and cause chronic neurodegeneration potentially for years after an initial brain injury.2,3 Methods. A custom-designed Controlled Cortical Impact (CCI) injury device was utilized on adult male C57B1/6 mice. Sham animals underwent the same procedure as injured mice except for the impact. In study 1, moderate-level CCI TBI mice were used in longitudinal T2-weighted MRI analysis 3, 6 and 12 months post-injury. Cortical tissue was harvested for biochemical analysis at 12 months post-injury. In study 2, moderate-level CCI TBI mice were used for histological analysis at 1, 5, 12, or 52 weeks after injury. Sham-injured mice were used as non-injured controls at 1 week and 52 weeks post-injury. Results. MRI study demonstrated that lesion volumes expanded significantly from 17.81 1.99 mm3 at 6 months post-injury to 24.09 1.58 mm3 at 12 months post-injury (p = 0.0314, paired Student t-test).3 Stereological analysis of microglial number and activation status showed significant increase in numbers of activated microglia in the 1-week, 5-week, and 12-week TBI groups (p < 0.001 for each) versus the sham-injured group.3 There was a significant increase in the number of activated microglia in the 52-week TBI group versus the 1-week or 52-week sham-injured groups (p < 0.01 for each).3 Microglia remained chronically activated through 1 year post-injury and did not return to sham-injured levels.3 Conclusion. Ongoing neuroinflammatory processes persist for up to 1 year after a single moderate-TBI in adult male mice. This study suggests a link between TBI-induced neuroinflammation and progressive neurodegeneration, which indicates a therapeutic window for treatment of TBI to be longer than initially expected.
- Gardner AJ, Zafonte R. Neuroepidemiology of traumatic brain injury. Handbook of Clinical Neurology. 2016;138(207-223). doi:10.1016/B978-0-12-802973-2.00012-4.
- Loane DJ, Kumar A. Microglia in the TBI Brain: The Good, The Bad, And The Dysregulated. Experimental neurology. 2016;275(0 3):316-327. doi:10.1016/j.expneurol.2015.08.018.
- Loane DJ, Kumar A, Stoica BA, Cabatbat R, Faden AI. Progressive Neurodegeneration after Experimental Brain Trauma: Association with Chronic Microglial Activation. Journal of neuropathology and experimental neurology. 2014;73(1):14-29. doi:10.1097/NEN.0000000000000021.