TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice

Cell Rep. 2019 Apr 9;27(2):549-560.e6. doi: 10.1016/j.celrep.2018.12.055.


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.

Keywords: NF-κB; TRIM9; neuroinflammation; stroke.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Cells, Cultured
  • Female
  • HEK293 Cells
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Neuroprotection
  • Phosphorylation
  • Stroke / genetics
  • Stroke / metabolism*
  • Tripartite Motif Proteins / biosynthesis*
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / biosynthesis*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism


  • Nerve Tissue Proteins
  • Tripartite Motif Proteins
  • TRIM9 protein, human
  • Trim9 protein, mouse
  • Ubiquitin-Protein Ligases