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Inhibition of miR-155 Limits Neuroinflammation and Improves Functional Recovery After Experimental Traumatic Brain Injury in Mice

  • Rebecca J. Henry
  • Sarah J. Doran
  • James P. Barrett
  • Victoria E. Meadows
  • Boris Sabirzhanov
  • Bogdan A. Stoica
  • David J. Loane
  • Alan I. Faden
Original Article

Abstract

Micro-RNAs (miRs) are short, noncoding RNAs that negatively regulate gene expression at the post-transcriptional level and have been implicated in the pathophysiology of secondary damage after traumatic brain injury (TBI). Among miRs linked to inflammation, miR-155 has been implicated as a pro-inflammatory factor in a variety of organ systems. We examined the expression profile of miR-155, following experimental TBI (controlled cortical impact) in adult male C57Bl/6 mice, as well as the effects of acute or delayed administration of a miR-155 antagomir on post-traumatic neuroinflammatory responses and neurological recovery. Trauma robustly increased miR-155 expression in the injured cortex over 7 days. Similar TBI-induced miR-155 expression changes were also found in microglia/macrophages isolated from the injured cortex at 7 days post-injury. A miR-155 hairpin inhibitor (antagomir; 0.5 nmol), administered intracerebroventricularly (ICV) immediately after injury, attenuated neuroinflammatory markers at both 1 day and 7 days post-injury and reduced impairments in spatial working memory. Delayed ICV infusion of the miR-155 antagomir (0.5 nmol/day), beginning 24 h post-injury and continuing for 6 days, attenuated neuroinflammatory markers at 7 days post-injury and improved motor, but not cognitive, function through 28 days. The latter treatment limited NADPH oxidase 2 expression changes in microglia/macrophages in the injured cortex and reduced cortical lesion volume. In summary, TBI causes a robust and persistent neuroinflammatory response that is associated with increased miR-155 expression in microglia/macrophages, and miR-155 inhibition reduces post-traumatic neuroinflammatory responses and improves neurological recovery. Thus, miR-155 may be a therapeutic target for TBI-related neuroinflammation.

Key Words

Traumatic brain injury miR-155 microglial activation neuroinflammation neuroprotection 

Notes

Funding Information

This work was supported by NIH R01 NS037313 (AIF), R01 NS082308 (DJL), and T32 AI095190 (SJD).

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2018

Authors and Affiliations

  • Rebecca J. Henry
    • 1
  • Sarah J. Doran
    • 1
  • James P. Barrett
    • 1
  • Victoria E. Meadows
    • 1
  • Boris Sabirzhanov
    • 1
  • Bogdan A. Stoica
    • 1
  • David J. Loane
    • 1
    • 2
  • Alan I. Faden
    • 1
    • 3
  1. 1.Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) CenterUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Department of AnesthesiologyUniversity of Maryland School of MedicineBaltimoreUSA
  3. 3.Department of AnesthesiologyUniversity of Maryland School of MedicineBaltimoreUSA

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