Farzi Aitak, Reichmann Florian, Meinitzer Andreas, Mayerhofer Raphaela, Jain Piyush, Hassan Ahmed M, Fröhlich Esther E, Wagner Karin, Painsipp Evelin, Rinner Beate, Holzer Peter
Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
Brain Behav Immun. 2015 Feb;44:106-20. doi: 10.1016/j.bbi.2014.08.011. Epub 2014 Sep 11.
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.
Toll样受体（TLRs）和核苷酸结合寡聚化结构域（NOD）样受体（NLRs）是细菌细胞壁成分的感受器，可触发免疫反应。TLR4激动剂脂多糖（LPS）是一种强大的免疫激活剂，可导致疾病和情绪低落。NOD激动剂活性较低，但可使免疫细胞致敏，增强LPS诱导的细胞因子产生。由于对NOD和TLR在体内共同激活的影响研究较少，因此在雄性C57BL/6N小鼠中研究了NOD1激动剂FK565和NOD2激动剂胞壁酰二肽（MDP）单独以及与LPS联合使用对免疫激活、脑功能和疾病行为的影响。在注射LPS（0.1或0.83mg/kg）前4小时腹腔注射FK565（0.001或0.003mg/kg）或MDP（1或3mg/kg），从运动、探索、食物摄入和体温下降可推断出，这显著加重并延长了LPS诱发的疾病行为。单独使用时，FK565和MDP的作用较小。FK565或MDP与LPS联合使用诱导的疾病行为加重与促炎细胞因子（IFN-γ、IL-1β、IL-6、TNF-α）的血浆蛋白和脑mRNA水平升高以及犬尿氨酸的血浆水平升高平行。脑中c-Fos的免疫组化显示，NOD2与TLR4协同作用导致与疾病相关的脑细胞核激活增加。这些数据表明，NOD1或NOD2与TLR4协同作用会加剧对周围免疫刺激的免疫、疾病和脑反应。我们的研究结果表明，NLRs和TLRs在免疫细胞水平上的已知相互作用扩展到了影响脑功能和行为的相互作用。
