Summary: After TBI, the intrinsic recycling functions of the brain’s immune cells are significantly slowed, allowing waste products to build up and interfering with injury recovery. Treatment with rapamycin helps reduce neuroinflammation and promotes cellular recycling after TBI.
Source: University of Maryland
About 1.5 million people in the United States each year survive a traumatic brain injury from a fall, car accident, or sports injury, which can cause immediate and long-term disability.
University of Maryland School of Medicine (UMSOM) researchers wanted to better understand what happens in the brain during trauma, so they conducted a study on mice to determine how different types of brain cells in mice respond to severe trauma.
A new study published in the January issue of AutophagyThey found that after a traumatic brain injury, the internal recycling function of the brain’s immune system cells slows dramatically, causing waste products to build up and interfering with recovery from injury.
The researchers also found that treating traumatic brain injury mice with a drug to promote cellular recycling improved the mice’s ability to recover from the injury and solve the water maze, a measure of the mice’s memory function.
“Many drugs and potential solutions have been proposed to treat traumatic brain injury, but none have ever worked in practice,” said lead researcher Marta Lipinski, PhD, associate professor of anesthesiology and anatomy and neurobiology at UMSOM and member of Shock, Trauma. , and the Anesthesiology Research (STAR) Center at the University of Maryland Medical Center (UMMC).
“It may be that designing drugs for patients that promote this cellular recycling can reverse or prevent damage from traumatic brain injury, as we’ve seen in our animal studies. We’re learning more about the molecular and cell biology processes in trauma, so we can find solutions.” Can use a more directed approach to development.”
Body cells regularly recycle their own worn-out or damaged parts that accumulate through normal wear and tear, infection or injury in a process known as autophagy. Most cells in the brain use this process to clean up their own waste and recycle it on a small scale.
In a previous study, Dr. Lipinski’s group showed that traumatic brain injury reduces the ability of neurons—the cells that send electrical impulses—to recycle their own damaged parts, causing these neurons to die.
However, some cells in the brain can perform greater functions of recycling, such as the brain’s resident immune cells known as microglia, which can engulf, digest, and recycle completely damaged or dead cells in tissue.
After a traumatic brain injury, white blood cells—normally excluded by the blood-brain barrier—can also enter the brain and work alongside microglia cells to eat and remove damaged cells.
For this new study, Dr. Lipinski’s team focused on immune cells — microglia and white blood cells — in the brain after traumatic brain injury and found that, like neurons, their recycling function was also suppressed.
“Dr. Lipinski’s discovery of suppression of the recycling function of both neurons and immune cells demonstrates how important it is for neuroscientists to fully understand the complex systems involved in a traumatic brain injury,” said Dean Mark Gladwin, MD, vice president for medical affairs. University of Maryland, Baltimore, and John Z. and Akiko K. Bowers is a distinguished professor at UMSOM.
“Developing effective drugs to treat traumatic brain injury requires a deeper understanding of these cell-to-cell interactions and the impact each cell type has on the brain ecosystem.”
To demonstrate the full impact of the recycling process on traumatic brain injury and recovery, Dr. Lipinski and his team blocked one of the proteins necessary for immune cell recycling to occur in the brains of mice with brain injuries. These mice experienced greater suppression of their cell recycling processes, leading to more inflammation in their brains.
They performed even worse, as measured by their ability to solve the water maze, than rats with brain injury alone. These findings suggested that the regenerative function of brain immune cells is essential for recovery after brain injury. Conversely, increasing it may reduce the impact of trauma.
To test this, the researchers used a drug, rapamycin (commonly used as a cancer drug or to prevent organ rejection), to promote cellular recycling in the brains of mice that had suffered a traumatic brain injury. The researchers found that with the treatment, the mice had lower levels of inflammation in their brains, and these mice did better at navigating the water maze.
“The drug we used in our study blocks a set of proteins that are important for cell regeneration in the body, so it can’t be used for long periods of time,” said Dr. Lipinski. “We need to continue this line of research to identify the exact mechanism by which autophagy protects against neuronal damage in order to find more targeted drugs that enhance this process without targeting proteins essential for brain regeneration.”
Financing: This research was funded by grants from the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS094527, R01NS091218, R01NS115876) of the National Institutes of Health.
Dr. with this news of TBI research
Author: Vanessa McMains
Source: University of Maryland
Contact: Vanessa McMains – University of Maryland
Image: Image is in public domain
Original Research: Access to all.
“Inhibition of autophagy in microglia and macrophages enhances innate immunity and worsens the outcome of brain injury” by Marta Lipinski et al. Autophagy
abstract
Inhibition of autophagy in microglia and macrophages enhances innate immunity and worsens the outcome of brain injury
Excessive and prolonged neuroinflammation after traumatic brain injury (TBI) contributes to long-term tissue damage and poor functional outcome.
However, the mechanisms contributing to the increased inflammatory response after brain injury are poorly understood.
Our previous work showed that macroautophagy/autophagy flux is inhibited in neurons following TBI in rats and contributes to neuronal cell death.
In the present study, we demonstrated that autophagy is inhibited in activated microglia and infiltrating macrophages and potentiates injury-induced neuroinflammatory responses.
Macrophage/microglia-specific knockout of essential autophagy genes Becn1 Neuroinflammation after TBI leads to overall exacerbations. Specifically, we observed overactivation of innate immune responses, including both type-I interferon and inflammatory pathways.
Defects in microglial and macrophage autophagy after injury were associated with reduced phagocytic clearance of danger/damage-associated molecular patterns (DAMP) responsible for activating cellular innate immune responses.
Our data also demonstrated a role for precision autophagy in the targeting and degradation of innate immune pathway components such as the NLRP3 inflammasome.
Finally, inhibition of microglial/macrophage autophagy leads to increased neurodegeneration and worse long-term cognitive outcomes after TBI. Conversely, increasing autophagy by treatment with rapamycin reduced inflammation and improved outcome in wild-type mice after TBI.
Overall, our work shows that inhibition of autophagy in microglia and infiltrating macrophages contributes to excessive neuroinflammation after brain injury and may prevent resolution of inflammation and tissue regeneration in the long term.
