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

被引:50
作者
Zimmerman, G. [1 ]
Shaltiel, G. [1 ]
Barbash, S. [1 ]
Cohen, J. [2 ,3 ]
Gasho, C. J. [4 ]
Shenhar-Tsarfaty, S. [1 ,5 ,6 ]
Shalev, H. [7 ]
Berliner, S. A. [5 ,6 ]
Shelef, I. [4 ]
Shoham, S. [8 ]
Friedman, A. [2 ,3 ]
Cohen, H. [9 ]
Soreq, H. [1 ]
机构
[1] Hebrew Univ Jerusalem, Inst Life Sci, Edmond & Lily Safra Ctr Brain Sci, IL-91904 Jerusalem, Israel
[2] Ben Gurion Univ Negev, Dept Physiol, IL-84105 Beer Sheva, Israel
[3] Ben Gurion Univ Negev, Zlotowski Ctr Neurosci, IL-84105 Beer Sheva, Israel
[4] Ben Gurion Univ Negev, Dept Radiol, IL-84105 Beer Sheva, Israel
[5] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, IL-69978 Tel Aviv, Israel
[6] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel
[7] Soroka Med Ctr, Dept Psychiat, IL-84101 Beer Sheva, Israel
[8] Herzog Hosp, Res Dept, Jerusalem, Israel
[9] Ben Gurion Univ Negev, Anxiety & Stress Res Unit, Negev, Israel
基金
以色列科学基金会;
关键词
inflammation; innate immune system; NF kappa B; oligonucleotide; post-traumatic stress; TLR9; C-REACTIVE PROTEIN; STRESS-DISORDER; ANIMAL-MODEL; BRAIN; ACETYLCHOLINESTERASE; MEMORY; TOLL-LIKE-RECEPTOR-9; INTERLEUKIN-1-BETA; NEUROINFLAMMATION; SUPPRESSION;
D O I
10.1038/tp.2012.4
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
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 NF kappa B-mediated enhancement of inflammatory reactions in the post-traumatic phenotype, we found association of serum interleukin-1 beta increases with symptoms severity and volumetric brain changes in post-traumatic stress disorder patients. In predator scent-stressed mice, the moderate NF kappa B-activating oligonucleotides mEN101 and its human ortholog BL-7040, but not the canonic NF kappa B activator oligonucleotide ODN1826, induced anxiolytic effects. In stressed mice, peripherally administered mEN101 prevented delayed stress-inducible serum interleukin-1 beta 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 NF kappa B-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. Translational Psychiatry (2012) 2, e78; doi:10.1038/tp.2012.4; published online 21 February 2012
引用
收藏
页码:e78 / e78
页数:11
相关论文
共 51 条
[1]   The role of the read through variant of acetylcholinesterase in anxiogenic effects of predator stress in mice [J].
Adamec, Robert ;
Head, David ;
Soreq, Hermona ;
Blundell, Jacqueline .
BEHAVIOURAL BRAIN RESEARCH, 2008, 189 (01) :180-190
[2]   Pivotal Role of TLR4 Receptors in Alcohol-Induced Neuroinflammation and Brain Damage [J].
Alfonso-Loeches, Silvia ;
Pascual-Lucas, Maya ;
Blanco, Ana M. ;
Sanchez-Vera, Irene ;
Guerri, Consuelo .
JOURNAL OF NEUROSCIENCE, 2010, 30 (24) :8285-8295
[3]  
[Anonymous], 2000, Diagnostic and statistical manual of mental disorders, V4th
[4]   Treatment of human myasthenia gravis with oral antisense suppression of acetylcholinesterase [J].
Argov, Z. ;
Mckee, D. ;
Agus, S. ;
Brawer, S. ;
Shlomowitz, N. ;
Ben Yoseph, O. ;
Soreq, H. ;
Sussman, J. D. .
NEUROLOGY, 2007, 69 (07) :699-700
[5]   BLOOD TO BRAIN TRANSPORT OF INTERLEUKIN LINKS THE IMMUNE AND CENTRAL NERVOUS SYSTEMS [J].
BANKS, WA ;
KASTIN, AJ .
LIFE SCIENCES, 1991, 48 (25) :PL117-PL121
[6]  
Berlant Jeffrey, 2003, Curr Opin Investig Drugs, V4, P37
[7]   Psychometric properties of the PTSD checklist (PCL) [J].
Blanchard, EB ;
JonesAlexander, J ;
Buckley, TC ;
Forneris, CA .
BEHAVIOUR RESEARCH AND THERAPY, 1996, 34 (08) :669-673
[8]   Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD [J].
Bonne, O ;
Brandes, D ;
Gilboa, A ;
Gomori, JM ;
Shenton, ME ;
Pitman, RK ;
Shalev, AY .
AMERICAN JOURNAL OF PSYCHIATRY, 2001, 158 (08) :1248-1251
[9]   Unsupervised fuzzy clustering analysis supports behavioral cutoff criteria in an animal model of posttraumatic stress disorder [J].
Cohen, H ;
Zohar, J ;
Matar, MA ;
Kaplan, Z ;
Geva, AB .
BIOLOGICAL PSYCHIATRY, 2005, 58 (08) :640-650
[10]   An animal model of posttraumatic stress disorder - The use of cut-off behavioral criteria [J].
Cohen, H ;
Zohar, J .
BIOBEHAVIORAL STRESS RESPONSE: PROTECTIVE AND DAMAGING EFFECTS, 2004, 1032 :167-178