What Is the Main Idea?
Long-lasting damage after a traumatic brain injury can be caused by excessive neuroinflammation in the brain. In the open access research article “MiR-124 Reduced Neuroinflammation after Traumatic Brain Injury by Inhibiting TRAF6”, published in the journal Neuroimmunomodulation, the authors discuss how the levels of a microRNA called miR-124 influence the extent of neuroinflammation after a traumatic brain injury and investigate the mechanisms involved.
What Else Can You Learn?
In this blog post, the effects of a traumatic brain injury on the brain and the role of neuroinflammation are discussed. The functions of RNAs, particularly microRNAs, are also described.
What Is Traumatic Brain Injury?
A traumatic brain injury can be caused by something piercing the skull and entering the brain tissue, or by a violent blow or jolt to the head or body (for example if a person is struck by an object or is involved in a vehicle accident). Although some traumatic brain injuries cause short-term or temporary problems, others can be fatal or lead to long-term disability. When a traumatic brain injury occurs, there are usually two phases of damage that affect the brain:
- The first, “primary” phase happens immediately when the trauma takes place and may include bleeding, brain swelling, and damage to nerve fibers.
- “Secondary” brain damage develops after the initial injury and may take hours or weeks to develop. Secondary damage can include an increase of pressure inside the skull (usually due to the brain swelling), reduced blood pressure or oxygen flow, a breakdown of the blood–brain barrier (which controls the movement of molecules and cells between the blood and the fluid that surrounds the nerve cells in the brain), and neuroinflammation.
What Is Neuroinflammation?
The term “neuroinflammation” describes inflammation (the process by which your body responds to an injury or a perceived threat, such as a bacterial infection) in the central nervous system (CNS; which consists of the brain and spinal cord). As with inflammation in the rest of the body, neuroinflammation is an essential process that plays a protective role after injury, exposure to toxins, or infection. However, neuroinflammation can be harmful if the level of inflammation is excessively high or it is activated for too long, and chronic (long-term or recurring) neuroinflammation is associated with the progression of neurodegenerative diseases such as multiple sclerosis, Parkinson disease, and Alzheimer disease.
Several processes are involved in neuroinflammation and microglia are one of the main cell types involved. They are specialized cells, making up around 10% of the total number of cells in the CNS, that regulate the development of the brain, maintain neuronal networks, and help repair injury. Microglia actively survey their environment and engulf foreign material, and dead or damaged cells, to prevent them from affecting other brain cells. They also produce cell signaling molecules called “cytokines” that can either promote or inhibit inflammation.
When microglia become “activated” when infection or injury occurs, the profile of genes that are activated inside them changes rapidly and they begin to produce more pro-inflammatory cytokines (cytokines that promote inflammation) and other molecules. This is termed the “M1 phenotype” (the word “phenotype” means an observable characteristic) of microglia. Over time, microglia become “polarized” (changed) to the “M2 phenotype” and begin to secrete anti-inflammatory cytokines that reduce neuroinflammation and promote the repair of damaged tissue. The changes in gene activation that occur when microglia are activated and polarized can be detected by analyzing the levels of different types of RNA (ribonucleic acid).
What Is RNA?
Your genes are short sections of DNA (deoxyribonucleic acid) that carry the genetic information for the growth, development, and function of your body. Each gene carries the code for a protein or an RNA. There are several different types of RNA, each with different functions, and they play important roles in normal cells and the development of disease.
Messenger RNAs are single-stranded copies of genes that are made when a gene is switched on (expressed). They carry messages regarding which proteins should be made to the cell’s protein-making machinery. In a cell, long strings of double-stranded DNA are coiled up as chromosomes in a part of the cell called the nucleus. Chromosomes are too big to move out of the nucleus to the part of the cell where proteins are made, but messenger RNA copies of genes are small enough to get through.
MicroRNAs are much smaller than messenger RNAs. They do not code for proteins and instead play important roles in regulating genes, for example by inhibiting (silencing) gene expression by binding to complementary sequences in messenger RNA molecules, stopping their “messages” from being read, and preventing the proteins they code for from being made. Some microRNAs also activate signaling pathways inside cells, turning processes on or off.
What Did the Research Article Investigate?
After a traumatic brain injury, inactive microglia become active and migrate to the regions of the brain that surround the sites of injury. They produce and release pro-inflammatory cytokines and recruit immune cells that are circulating in the bloodstream to enter the brain, which amplifies neuroinflammation. Because this can become a problem and lead to secondary brain damage, the authors of the study are interested in exploring whether excessive neuroinflammation can be inhibited in some way.
Recent studies have reported that if a molecule called TLR4 (toll-like receptor 4; a receptor molecule that is found in cell membranes and that causes cells to start producing pro-inflammatory cytokines when activated) is prevented from working in the brain in a targeted way, less neuroinflammation develops after a traumatic brain injury. There is also evidence that the levels of a microRNA called miR-124 may be linked to the activation of TLR4.
The authors of the study investigated how the levels of miR-124 changed after traumatic brain injury and found that its expression was reduced, whereas an increase in miR-124’s expression promoted the polarization of microglia to the M2 phenotype, which reduces neuroinflammation. The activity of the TLR4 pathway was also reduced, and this was found to be because miR124 inhibited a molecule inside the microglia called TRAF6, which is part of the signaling pathway that is activated by TLR4. If the signal that is produced when TLR4 is activated cannot travel along this pathway, the activation of pro-inflammatory genes is prevented and the chance of excessive neuroinflammation developing is reduced.
Research like this raises the possibility of treating traumatic brain injury more effectively in the future. If excessive activation and, consequently, neuroinflammation can be prevented, for example by developing therapies that inhibit TLR4 or TRAF6, the risk of people who have a traumatic brain injury having secondary brain damage may be reduced, improving their chance of better recovery.