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.
Highlights
Post-traumatic stress disorder (PTSD) is a severe and longlasting anxiety disorder with recently increasing abundance and social and economic significance.[1]
Given the reports on the increase in PTSD of both IL-1 and IL-6, we used the summated serum IL1b and IL6 levels (designated ‘inflammatory load’, (Figure 1a)) to challenge the possibility that peripheral inflammation is correlated with PTSD symptoms severity
When divided into high and low inflammatory load by splitting the group in the median (Figure 1a), patients with high inflammatory load (n 1⁄4 9) showed increased re-experiencing (Po0.014, Figure 1b), arousal (Po0.022), overall Clinician-Administered PTSD Scale (Po0.05) and Montgomery-Asberg Depression Rating Scale (MADRS) (Po0.02) scores compared with PTSD patients with low inflammatory load (n 1⁄4 10)
Summary
Post-traumatic stress disorder (PTSD) is a severe and longlasting anxiety disorder with recently increasing abundance and social and economic significance.[1] Apart from their central nervous system impairments, PTSD patients suffer multiple peripheral pathologies,[2] including persistent inflammation. Hormones released during stress prepare the immune system to cope with physical injuries.[5] anxiety patients and rodents exposed to acute stressors both show elevated serum levels of pro-inflammatory cytokines (for example, interleukin (IL) -1b and IL-6).[6,7] apart from their protective immune functions, such peripheral cytokines access the brain and stimulate specific receptors.[8,9,10]
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