Mild traumatic brain injuries (mTBI), commonly occurring in accidents, sports, or violent incidents, can lead to persistent memory problems and an increased risk of dementia. Yet, effective therapies to counteract these long-term consequences are still lacking. Dr. Dr. Sergio Castro-Gomez, Early Career Research Group Leader at the Institute of Physiology II of the University Hospital Bonn (UKB), Neuroscience Clinician Scientist at the UKB Center for Neurology, and associated with the Excellence Cluster ImmunoSensation3 and the Transdisciplinary Research Area (TRA) „Present Pasts“ at the University of Bonn, has discovered together with colleagues that the ASC protein – a key component of cellular “panic buttons” – triggers prolonged inflammation in the mouse brain for up to 21 days after injury. By elucidating the inflammatory mechanisms underlying traumatic brain injury, the research team hopes to identify new targets for future therapeutic strategies. The study, published in the Journal of Clinical Investigation, lays the foundation for upcoming clinical trials.
Dr. Castro-Gomez, what exactly makes brain injuries so dangerous, in your assessment?
Dr. Dr. Sergio Castro-Gomez: “Every year, around three to five million people in the EU and the USA suffer a traumatic brain injury. Most of these are mild TBIs (mTBI) resulting from closed-head injuries caused by falls, traffic accidents, contact sports, or violence. Although mTBI symptoms can often resolve within days or weeks, up to 20% of those affected suffer from persistent physical, cognitive, and behavioral impairments. These can lead to a reduced quality of life and an increased risk of neuropsychiatric disorders, including mood disorders and dementia.”
How do you explain this?
Dr. Dr. Sergio Castro-Gomez: “The immediate effect of a brain injury from a fall or impact is damage to nerve cells. This triggers an alarm in the brain that activates the immune system and sets neuroinflammation in motion. In principle, inflammation serves a beneficial purpose. However, if it is too intense or persists for too long, it can cause further damage itself.”
In your study, you discovered that the ASC protein plays a central role in maintaining so-called neuroinflammation. How does this work?
Dr. Dr. Sergio Castro-Gomez: “Our immune cells contain small emergency response systems called inflammasomes. When an alarm is triggered, the ASC protein helps activate these ‘panic buttons’ by forming aggregates, which leads to the production of inflammatory mediators. While inflammasomes are known to be crucial for chronic inflammation of the central nervous system—clinically referred to as neuroinflammation—and secondary damage following trauma, their role in mild traumatic brain injuries remains poorly understood. In our study, we focused primarily on inflammasome activation and its functional significance in a closed-head injury model.”
What did you observe?
Dr. Dr. Sergio Castro-Gomez: “In mouse models lacking ASC, we observed that the activation of microglia—the immune cells of the central nervous system—and astrocytes, the star-shaped support cells in brain tissue, was significantly reduced. Additionally, fewer inflammatory mediators such as interleukin-1β were produced. The mice also exhibited fewer memory deficits in behavioral tests. Conversely, ASC aggregates spread extensively and exacerbated tissue damage. Our findings thus demonstrate that the inflammasome adapter protein ASC is a key driver of neuroinflammatory responses and cognitive impairments following mild traumatic brain injury.”
Do ASC blockers have the potential to stop inflammation and thus promote healing?
Dr. Dr. Sergio Castro-Gomez: “Further research is needed to gain a comprehensive understanding of the precise temporal involvement of inflammasomes across different injury severities and risk factors for neurodegeneration. However, even based on our current findings, pharmacological interventions targeting ASC could help mitigate neuroinflammation and potentially enhance neuroprotection. This could improve recovery after brain injury and prevent further neurodegeneration and functional impairments.”
Institutions Involved and Funding:
In addition to the University Hospital Bonn (UKB) and the University of Bonn, the University of Luxembourg also participated in this research. This work was supported by the Alzheimer Forschung Initiative e.V., the Hertie Network of Excellence in Clinical Neuroscience, the Neuroscience Clinician Scientist and BONFOR Programs of the Medical Faculty Bonn, the ImmunoSensation3 Cluster of Excellence, and the PEARL Program of the Luxembourg National Research Fund (FNR).
Publication:
Tao Li, Sergio Castro-Gomez et al.: Inflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury mode; Journal of Clinical Investigation; (DOI: 10.1172/JCI199818)
Contact:
Department of Parkinson, Sleep and Movement Disorders
University Hospital Bonn
TRA „Present Pasts“, University Bonn
Dr. Dr. Sergio Castro-Gomez
Phone: 0228 287-11269
E-Mail: Sergio.Castro-Gomez@ukbonn.de
Press contact:
Dr. Inka Väth
Deputy Press Officer at the University Hospital Bonn (UKB)
Communications and Media Office at Bonn University Hospital
Phone: (+49) 228 287-10596
E-mail: inka.vaeth@ukbonn.de
