Mast cell-dependent anorexia and hypothermia induced by mucosal activation of Toll-like receptor 7
Mast cell-dependent anorexia and hypothermia induced by mucosal activation of Toll-like receptor 7
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DOI：
10.1152/ajpregu.00527.2007
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发表时间：
2008-07-01
影响因子：
2.8
通讯作者：
Corr, Maripat
中科院分区：
文献类型：
--
作者：
Hayashi, Tomoko;Cottam, Howard B.;Corr, Maripat
系统性病毒感染在疾病行为中产生一系列高度调节的反应，如发热、厌食和厌食。Toll样受体（TLR）7在感染期间由病毒RNA激活，有效地刺激先天性和适应性免疫应答，从而帮助病毒清除。然而，TLR 7激活的生理后果尚未得到彻底研究。在这些实验中，我们使用有效的合成TLR 7配体9-苄基-8-羟基-2-（2-甲氧基乙氧基）腺嘌呤（SM 360320; 1V 136）来研究TLR 7在遗传上确定的小鼠品系中激活的后果。经鼻、胃内或腹膜内途径给药可引起一过性食欲减退、食欲减退和体温过低。对突变小鼠品系的分析表明，这些作用依赖于TLR 7、其衔接蛋白MyD 88和TNF-α的表达，而不依赖于IL-1 β、IL-6和环氧合酶-1（COX 1）。肥大细胞和COX 2也暗示了部分作用。虽然血浆TNF-α水平显着较高的全身给药后，行为的影响是最大的，当代理商给药到粘膜。已知组织和粘膜肥大细胞表达高水平的TLR 7并在TLR 7连接后快速释放TNF-α。缺乏组织肥大细胞的小鼠，W/W（v），在TLR 7激活后厌食症明显减少，并且这种反应随着肥大细胞重建而恢复。因此，我们的研究结果表明，组织肥大细胞可能发挥作用的粘膜激活TLR 7诱导的厌食症。
Systemic viral infections produce a highly regulated set of responses in sickness behavior, such as fever, anorexia, and adipsia. Toll-like receptor (TLR)7, activated by viral RNA during infection, potently stimulates the innate and adaptive immune responses that aid in viral clearance. However, the physiological consequences of TLR7 activation have not been thoroughly studied. In these experiments, we used a potent synthetic TLR7 ligand, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320; 1V136), to investigate the consequences of TLR7 activation in genetically defined strains of mice. Administration of the drug by the nasal, intragastric, or intraperitoneal routes caused transient hypophagia, hypodypsia, and hypothermia. Analyses of mutant mouse strains indicated that these effects were dependent on the expression of TLR7, its adaptor protein MyD88, and TNF-alpha, and independent of IL-1 beta, IL-6 and cyclo-oxygenase-1(COX1). Partial roles were also implied for mast cells and COX2. Although plasma TNF-alpha levels were significantly higher after systemic drug delivery, the behavioral effects were maximal when the agent was administered to the mucosa. Tissue and mucosal mast cells are known to express high levels of TLR7 and to rapidly release TNF-alpha upon TLR7 ligation. Mice deficient in tissue mast cells, W/W(v), had significantly less anorexia after TLR7 activation, and this response was restored with mast cell reconstitution. Our results thus suggest that tissue mast cells may play a role in the anorexia induced by mucosal activation of TLR7.