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

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 7days. Similar TBI-induced miR-155 expression changes were also found in microglia/macrophages isolated from the injured cortex at 7days post-injury. A miR-155 hairpin inhibitor (antagomir; 0.5nmol), administered intracerebroventricularly (ICV) immediately after injury, attenuated neuroinflammatory markers at both 1day and 7days post-injury and reduced impairments in spatial working memory. Delayed ICV infusion of the miR-155 antagomir (0.5nmol/day), beginning 24h post-injury and continuing for 6days, attenuated neuroinflammatory markers at 7days post-injury and improved motor, but not cognitive, function through 28days. 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.