Summary: The TRIM9 gene may help to resolve neuroinflammation and promote recovery following ischemic stroke.
Could a medication someday help the brain heal itself after a stroke, or even prevent damage following a blow to the head? A new USC study lends support to the idea.
When a person has a stroke, the brain responds with inflammation, which expands the area of injury and leads to more disability. In the April 9 issue of Cell Reports, USC researchers describe a key gene involved with tamping down inflammation in the brain, as well as what happens when the injured brain gets an added boost of that gene.
The gene — called TRIM9 — is abundant in the youthful brain but grows scarce with age, just as people become more at risk from stroke. In a lab model of stroke, researchers found that older brains with low TRIM9 levels — or engineered brains missing the TRIM9 gene entirely — were prone to extensive swelling following stroke.
But when the scientists used a harmless virus to carry a dose of the gene directly into TRIM9-deficient brains, the swelling decreased dramatically and recovery improved.
Jae Jung, lead author and chair of the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC, says it’s unlikely that gene therapy delivered by viruses will become the go-to treatment for strokes, head injuries or encephalitis. It’s too slow, he said, and the best shot at treating stroke is within the first 30 minutes to one hour. Jung says the next step will be identifying what, exactly, flips on the switch for TRIM9 gene expression.
“Maybe there will be a way to chemically activate TRIM9 right after a stroke,” Jung said. “Or maybe a football player can take a medication that turns on TRIM9 gene expression right after they get a blow to the head.”
Not all inflammation in the brain is bad, Jung added. Inflammation plays a role in fighting infection and helps clear away dead tissue. But when it goes on too long, neurons die; inflammation causes the brain’s blood vessels to become permeable, allowing white blood cells to enter tissue where they don’t belong.
In addition to Jung, the paper’s other authors are Berislav Zlokovic and Zhen Zhao of the Zilkha Neurogenetic Institute at the Keck School; co-first authors Jianxiong Zeng and Yaoming Wang, Zhifei Luo Lin-Chun Chang, Ji Seung Yoo, Huan Yan, Younho Choi and Xiaochun Xie, all of the Keck School; Benjamin Deverman and Viviana Gradinaru of the California Institute of Technology; and Stephanie Gupton of the University of North Carolina at Chapel Hill.
Funding: The study was supported by the National Institutes of Health (grants CA200422, CA180779, DE023926, DE027888, DE28521, AI073099, AI116585, AI129496, AI140718, 9R01NS090904-16 and AI140705), the Hastings Foundation, the Fletcher Jones Foundation, the Alzheimer’s Association (grant NIRG-15-363387), the Whittier Foundation, the Cure for Alzheimer’s Fund (NS090904), Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease (reference 16 CVD 05 and GM108970), the Beckman Institute at Caltech through the Resource Center for CLARITY, Optogenetics and Vector Engineering, and an NIH Director’s New Innovator Award (DP20D017782).
About this neuroscience research article
Source: USC Media Contacts: Leigh Hopper – USC Image Source: The image is in the public domain.
TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice
Highlights • TRIM9 expression is increased in the peri-infarct area shortly after ischemic stroke • Trim9-deficiency mice are more vulnerable to ischemia than wild-type mice • AAV-mediated brain-wide TRIM9 expression ameliorates ischemic injury in mice
Summary Excessive and unresolved neuroinflammation is a key component of the pathological cascade in brain injuries such as ischemic stroke. Here, we report that TRIM9, a brain-specific tripartite motif (TRIM) protein, was highly expressed in the peri-infarct areas shortly after ischemic insults in mice, but expression was decreased in aged mice, which are known to have increased neuroinflammation after stroke. Mechanistically, TRIM9 sequestered β-transducin repeat-containing protein (β-TrCP) from the Skp-Cullin-F-box ubiquitin ligase complex, blocking IκBα degradation and thereby dampening nuclear factor κB (NF-κB)-dependent proinflammatory mediator production and immune cell infiltration to limit neuroinflammation. Consequently, Trim9-deficient mice were highly vulnerable to ischemia, manifesting uncontrolled neuroinflammation and exacerbated neuropathological outcomes. Systemic administration of a recombinant TRIM9 adeno-associated virus that drove brain-wide TRIM9 expression effectively resolved neuroinflammation and alleviated neuronal death, especially in aged mice. These findings reveal that TRIM9 is essential for resolving NF-κB-dependent neuroinflammation to promote recovery and repair after brain injury and may represent an attractive therapeutic target.