title: 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: The Edmond and Lily Safra Center for Brain Sciences, The Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors: G
authors: G
authors: Zimmerman
authors: G
authors: G
authors: Shaltiel
authors: S
authors: S
authors: Barbash
authors: J
authors: J
authors: Cohen
authors: C J
authors: CJ
authors: Gasho
authors: S
authors: S
authors: Shenhar-Tsarfaty
authors: H
authors: H
authors: Shalev
authors: S A
authors: SA
authors: Berliner
authors: I
authors: I
authors: Shelef
authors: S
authors: S
authors: Shoham
authors: A
authors: A
authors: Friedman
authors: H
authors: H
authors: Cohen
authors: H
authors: H
authors: Soreq
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D021621:Imaging, Three-Dimensional; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D013313:Stress Disorders, Post-Traumatic / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000235:genetics*
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9