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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.
This article was published in the following journal.
Name: Cell reports
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The application of repeated, brief periods of vascular occlusion at the onset of REPERFUSION to reduce REPERFUSION INJURY that follows a prolonged ischemic event. The techniques are similar to ISCHEMIC PRECONDITIONING but the time of application is after the ischemic event instead of before.
Ischemic injury to the OPTIC NERVE which usually affects the OPTIC DISK (optic neuropathy, anterior ischemic) and less frequently the retrobulbar portion of the nerve (optic neuropathy, posterior ischemic). The injury results from occlusion of arterial blood supply which may result from TEMPORAL ARTERITIS; ATHEROSCLEROSIS; COLLAGEN DISEASES; EMBOLISM; DIABETES MELLITUS; and other conditions. The disease primarily occurs in the sixth decade or later and presents with the sudden onset of painless and usually severe monocular visual loss. Anterior ischemic optic neuropathy also features optic disk edema with microhemorrhages. The optic disk appears normal in posterior ischemic optic neuropathy. (Glaser, Neuro-Ophthalmology, 2nd ed, p135)
Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing REPERFUSION INJURY.
A synuclein that is a major component of LEWY BODIES that plays a role in neurodegeneration and neuroprotection.
The physiological processes and techniques used by the body to prevent neuronal injury and degeneration in the central nervous system following acute disorders or as a result of chronic neurodegenerative diseases.
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Stroke - Cerebrovascular Disease (CVA)
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