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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Farzi, A; Reichmann, F; Meinitzer, A; Mayerhofer, R; Jain, P; Hassan, AM; Fröhlich, EE; Wagner, K; Painsipp, E; Rinner, B; Holzer, P.
Synergistic effects of NOD1 or NOD2 and TLR4 activation on mouse sickness behavior in relation to immune and brain activity markers.
Brain Behav Immun. 2015; 44(1):106-120 Doi: 10.1016/j.bbi.2014.08.011 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Farzi Aitak
Co-Autor*innen der Med Uni Graz
Fröhlich Esther Eleonore
Holzer Peter
JAIN Piyush
Mayerhofer Raphaela
Meinitzer Andreas
Reichmann Florian
Rinner Beate
Wagner Karin

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Toll-like receptors (TLRs) and nuclear-binding domain (NOD)-like receptors (NLRs) are sensors of bacterial cell wall components to trigger an immune response. The TLR4 agonist lipopolysaccharide (LPS) is a strong immune activator leading to sickness and depressed mood. NOD agonists are less active but can prime immune cells to augment LPS-induced cytokine production. Since the impact of NOD and TLR co-activation in vivo has been little studied, the effects of the NOD1 agonist FK565 and the NOD2 agonist muramyl dipeptide (MDP), alone and in combination with LPS, on immune activation, brain function and sickness behavior were investigated in male C57BL/6N mice. Intraperitoneal injection of FK565 (0.001 or 0.003mg/kg) or MDP (1 or 3mg/kg) 4h before LPS (0.1 or 0.83mg/kg) significantly aggravated and prolonged the LPS-evoked sickness behavior as deduced from a decrease in locomotion, exploration, food intake and temperature. When given alone, FK565 and MDP had only minor effects. The exacerbation of sickness behavior induced by FK565 or MDP in combination with LPS was paralleled by enhanced plasma protein and cerebral mRNA levels of proinflammatory cytokines (IFN-γ, IL-1β, IL-6, TNF-α) as well as enhanced plasma levels of kynurenine. Immunohistochemical visualization of c-Fos in the brain revealed that NOD2 synergism with TLR4 resulted in increased activation of cerebral nuclei relevant to sickness. These data show that NOD1 or NOD2 synergizes with TLR4 in exacerbating the immune, sickness and brain responses to peripheral immune stimulation. Our findings demonstrate that the known interactions of NLRs and TLRs at the immune cell level extend to interactions affecting brain function and behavior. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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Acetylmuramyl-Alanyl-Isoglutamine - pharmacology
Adjuvants, Immunologic - pharmacology
Animals -
Brain - drug effects
Brain - immunology
Brain - metabolism
Corticosterone - blood
Cytokines - blood
Cytokines - metabolism
Eating - drug effects
Illness Behavior - drug effects
Illness Behavior - physiology
Kynurenine - blood
Lipopolysaccharides - pharmacology
Male -
Mice -
Mice, Inbred C57BL -
Motor Activity - drug effects
Nod1 Signaling Adaptor Protein - agonists
Nod1 Signaling Adaptor Protein - physiology
Nod2 Signaling Adaptor Protein - agonists
Nod2 Signaling Adaptor Protein - physiology
Oligopeptides - pharmacology
Proto-Oncogene Proteins c-fos - metabolism
RNA, Messenger - metabolism
Toll-Like Receptor 4 - agonists
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Food intake
Muramyl dipeptide
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