Post-traumatic anxiety associates with failure of the innate immune receptor TLR9 to evade the pro-inflammatory NFκB pathway.

Abstract

Post-traumatic anxiety notably involves inflammation, but its causes and functional significance are yet unclear. Here, we report that failure of the innate immune system Toll-like receptor 9 (TLR9) to limit inflammation is causally involved with anxiety-associated inflammation and that peripheral administration of specific oligonucleotide activators of TLR9 may prevent post-traumatic consequences in stressed mice. Suggesting involvement of NFκB-mediated enhancement of inflammatory reactions in the post-traumatic phenotype, we found association of serum interleukin-1β increases with symptoms severity and volumetric brain changes in post-traumatic stress disorder patients. In predator scent-stressed mice, the moderate NFκB-activating oligonucleotides mEN101 and its human ortholog BL-7040, but not the canonic NFκB activator oligonucleotide ODN1826, induced anxiolytic effects. In stressed mice, peripherally administered mEN101 prevented delayed stress-inducible serum interleukin-1β increases while limiting stress-characteristic hippocampal transcript modifications and the anxiety-induced EGR1-mediated neuronal activation. Attesting to the TLR9 specificity of this response, BL-7040 suppressed NFκB-mediated luciferase in transfected cells co-expressing TLR9, but not other TLRs. Furthermore, TLR9-/- mice were mEN101 and BL-7040 resistant and presented unprovoked anxiety-like behavior and anxiety-characteristic hippocampal transcripts. Our findings demonstrate functional relevance of TLR9 in protecting stressed mammals from overreacting to traumatic experiences and suggest using oligonucleotide-mediated peripheral TLR9 activation to potentiate the innate immune system and prevent post-traumatic inflammation and anxiety.

• Authors: G Zimmerman, G Shaltiel, S Barbash, J Cohen, C J Gasho, S Shenhar-Tsarfaty, H Shalev, S A Berliner, I Shelef, S Shoham, A Friedman, H Cohen, H Soreq
• Journal: Translational psychiatry (Transl Psychiatry) Vol. 2 Pg. e78 (Feb 21 2012) ISSN: 2158-3188 [Electronic] United States
• PMID: 22832815 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• NF-kappa B
• TLR9 protein, human
• Toll-Like Receptor 9

Topics

• Adult
• Animals
• Female
• Hippocampus (pathology, physiopathology)
• Humans
• Image Interpretation, Computer-Assisted
• Imaging, Three-Dimensional
• Immunity, Innate (genetics)
• Inflammation (genetics)
• Inflammation Mediators (blood)
• Magnetic Resonance Imaging
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• NF-kappa B (genetics)
• Stress Disorders, Post-Traumatic (genetics)
• Toll-Like Receptor 9 (genetics)