New research examines how mild brain injury sparks early immune response

Scientists at The University of Texas Medical Branch (UTMB) have published a study in the peer-reviewed journal Proceedings of the National Academy of Sciences (PNAS) about the discovery of a biological pathway that helps explain how mild traumatic brain injury (mTBI) triggers an inflammation response in the brain that may play a critical role in recovery.

Funded by the National Institutes of Health (NIH), the U.S. National Science Foundation (NSF), and The Institute for Rehabilitation and Research (TIRR) Foundation's Mission Connect, the study paves the way for additional research into the role of inflammation in traumatic brain injury and points to a potential biomarker for mTBI.

Mild traumatic brain injury, or concussion, accounts for nearly 90% of all head injuries and affects millions of people each year through falls, motor vehicle crashes, and contact sports. While symptoms may be subtle, mTBI can lead to persistent memory issues and cognitive and behavioral problems. Persistent neuroinflammation is a major contributor to cognitive and motor impairment.

The links between early neuronal damage and the brain's immune response have remained poorly understood, but the significance of concussive injury has become a topic of public interest over the last few years, especially in the context of sports injuries. Children's brains can be especially vulnerable to injury. Chronic traumatic encephalopathy (CTE), which can cause dementia-like symptoms, has been diagnosed in high school and college athletes.

In this study, UTMB researchers were interested in the type of concussion that occurs when impact does not penetrate the brain but causes it to move inside the skull, resulting in injury.

The researchers found that mitochondrial DNA released from injured neurons acts as a danger signal that activates microglia, the brain's resident immune cells. The findings identify a key mechanism linking neuronal injury to immune activation and suggest new strategies to improve recovery after mTBI.

"Our study showed that even during mild head injury, neurons release mitochondrial DNA that, due to its bacterial origin, is a potent pro-inflammatory molecule," said Bartosz Szczesny, PhD, associate professor with the UTMB Department of Ophthalmology and Visual Sciences. "Interestingly, these mitochondrial DNA fragments are packed within neuronal-derived small vesicles, called extracellular vesicles, that are picked up by brain immune cells, particularly microglia, and cause their activation."

A danger signal from damaged mitochondria

The research team found that in mice, mTBI damages mitochondrial DNA - but not nuclear DNA - in neurons. Mitochondria are the energy-producing structures inside cells, and their DNA is especially vulnerable to injury.

The damaged mitochondrial DNA was found to be packaged into tiny extracellular vesicles and released from neurons, where it is taken up by microglia. Once inside the immune cell, the mitochondrial DNA binds to a cytoplasmic sensor protein, triggering an inflammatory signaling cascade.

This activation leads to the production of inflammatory molecules, which are part of the brain's early immune response to injury.

Early inflammation can be protective

To better understand the role of this pathway, the researchers studied mice lacking the cytoplasmic sensor protein known as Z-DNA binding protein 1, or ZBP1.

The researchers noted reduced microglial activation and lower inflammation early in their observation of these mice. However, they found more severe memory-related cognitive deficits later.

The findings help explain why microglial activation in mTBI differs from the prolonged and damaging inflammation seen in more serious brain injuries. In mTBI, immune activation is more temporary and more localized, supporting repair rather than driving long-term neurodegeneration.

Implications for diagnosis and future therapies

The study also showed that mitochondrial DNA and neuronal markers could be detected in the blood shortly after injury, raising the possibility that these signals could one day inform blood-based biomarkers for mTBI. A simple blood test could then be used to help diagnose concussions.

While the research was conducted in preclinical models rather than humans, it highlights a promising target for future therapeutic strategies aimed at improving recovery without suppressing beneficial immune responses.

"Our study has strong potential to be used in real-world care," Szczesny said. "Short-term activation of immune cells can be helpful, but long-term activation can be harmful. Thus, inhibition of the identified pathway post-acute phase can have a beneficial effect, blocking chronic neuroinflammatory responses. This is particularly important as currently there are no therapies for chronic neuroinflammation.

"We also found higher levels of mitochondrial DNA circulating in the blood. Interestingly, we showed earlier that the level of mitochondrial DNA is severity dependent. We are now testing whether mitochondrial DNA could be used as a biomarker to measure the severity of traumatic brain injury."

As concussion protocols become an integral part of sports, including youth sports, a blood test could serve as an additional tool to diagnose mTBIs.

Additional diagnostic tools for brain injuries might help athletes avoid catastrophic consequences like second impact syndrome - a type of fatal brain swelling that can occur when a second concussion happens before a prior concussion has healed.

"Our current efforts are focused on developing a new model that enables selective manipulation of ZBP1 expression in microglia," Szczesny said. "This model will be essential for future studies aimed at reducing inflammation during the post-acute phase of TBI and for testing potential pharmacological interventions. At the same time, we are continuing to evaluate mitochondrial DNA as a potential biomarker for TBI. In parallel, we are also investigating the role of the mitochondrial DNA-ZBP1 pathway beyond head injury, including its relevance in glaucoma."

Michela Marcatti, PhD, a research scientist in the UTMB Department of Neurology and first author of the article, agreed with Szczesny's vision for future research goals.

"This study highlights how extracellular vesicles can mediate communication between injured neurons and immune cells in the brain following mild traumatic brain injury," Marcatti said. "Understanding these early signaling events may help identify biomarkers and therapeutic targets aimed at improving recovery while preventing chronic neuroinflammation."

Other researchers who contributed to the study are Javier Allende Labastida, Christina Payne, Paula Villarreal, Olivia D. Solomon, Gracie Vargas, and Ping Wu of the UTMB Department of Neurobiology; Tony Zifeng Tang and Nora Schwartz of the UTMB Department of Ophthalmology and Visual Services; and Akbar Ahmad of the UTMB Department of Anesthesiology.