A team of researchers at the University of Maryland School of Medicine (UMSOM) have found that after traumatic brain injury, the brain’s immune system cells’ internal recycling function slows dramatically, allowing waste products to build up and interfere with recovery from injury. They also found that treating mice that had traumatic brain injury with a drug to promote cellular recycling improved the mice’s ability to recover from injury and solve a water maze, a measure of memory function in mice.
The researchers believe that these findings could lead to the development of new drugs to treat traumatic brain injury. The study’s lead researcher, Marta Lipinski, Associate Professor of Anesthesiology and Anatomy & Neurobiology at UMSOM and a member of the Shock, Trauma, and Anesthesiology Research (STAR) Center at the University of Maryland Medical Center (UMMC), set aside some time to discuss the paper.
What initially prompted your interest in studying the effects of traumatic brain injury (TBI) and its impact on different types of brain cells?
TBI is a very common problem – estimated lifetime probability of a person in the US having TBI requiring medical attention is about 1 in 10. In order to develop treatments for all these patients, it is important we study the mechanisms contributing to brain damage in TBI.
Could you explain more about the brain’s recycling process known as autophagy? How does this process contribute to the overall health of the brain?
Autophagy is very important for the overall brain health. Just as every person has to take out garbage and recycle to keep their house clean, so does each cell in the brain. The cells use autophagy to capture and get rid of components that are not functioning properly. Without autophagy, brain cells accumulate things like damage organelles and misfiled proteins that prevent the cells from functioning properly and staying healthy. And the whole brain suffers as a result.
Your study found that traumatic brain injury slows down the brain’s immune system cells’ internal recycling function. Can you explain how this can negatively impact the recovery process after a TBI?
Without autophagy, the damaged brain cells are unable to remove damaged components and return to health. In neurons, that leads to death of additional cells. In immune cells, it makes them more pro-inflammatory. Both neuronal cell death and inflammation make recovery after TBI more difficult.
Can you elaborate on the role of microglia, the brain’s resident immune cells, in maintaining brain health, particularly in the aftermath of a TBI?
The normal role of immune cells, including microglia, is to detect any intruding pathogens or tissue damage and to get rid of them so the organism can heal. So, a bit of inflammation is a normal part of response to injury: like when you cut your finger there is a bit of inflammation before the wound can heal. The problem with TBI is that instead of going away and allowing tissue recovery, the inflammation persists and becomes pathogenic.
You mentioned that after a TBI, white blood cells—normally excluded by the blood-brain barrier—get into the brain. How does this affect the brain’s recovery process?
The peripheral immune cells infiltrating the brain after TBI work together with microglia to increase levels of inflammation. The inflammatory signal gets amplified and makes recovery more difficult.
Your study blocked one of the essential proteins needed for the immune cell’s recycling function in mice with a TBI then used rapamycin. What did you find?
When we blocked autophagy, the cellular recycling process, in microglia the recovery after TBI was worse. That tells us that having normal autophagy is beneficial. When we increased levels of autophagy by treating mice with rapamycin, the recovery was better. This suggests that increasing autophagy may be a potential future treatment for TBI patients. But we really need to understand more about this process beforehand.
Finally, what are the next steps for your research?
We are working to understand both why autophagy is inhibited in the immune cells and why that causes increased levels of inflammation. That will be necessary before autophagy can be targeted therapeutically. We are also looking at what happens in the long-term. TBI is a known factor predisposing to development of neurodegenerative disease later in life and we want to know if inhibition of autophagy may contribute to this process as well.
IMAGE CREDIT: EKATERINA BOLOVTSOVA.
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