Central control of fever and female body temperature by RANKL/RANK
Central control of fever and female body temperature by RANKL/RANK
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DOI：
10.1038/nature08596
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发表时间：
2009-11-26
期刊：
影响因子：
64.8
通讯作者：
Penninger, Josef M.
中科院分区：
文献类型：
--
作者：
Hanada, Reiko;Leibbrandt, Andreas;Penninger, Josef M.
NF-κ B配体的受体激活剂（TNFSF 11，也称为RANKL、OPGL、TRANCE和ODF）及其肿瘤坏死因子（TNF）家族受体RANK是骨重建、淋巴结器官发生和泌乳乳腺形成的重要调节剂（1-4）。RANKL和RANK也在中枢神经系统中表达（5，6）。然而，RANKL/RANK在脑中的功能相关性完全未知。在这里，我们报告RANKL和RANK在大脑中起着重要作用。在小鼠和大鼠中，中枢RANKL注射均引发重度发热。使用组织特异性Nestin-Cre和GFAP-Cre rank（floxed）deleter小鼠，将发热反应中RANK的功能遗传映射到星形胶质细胞。重要的是，Nestin-Cre和GFAP-Cre rank（floxed）deleter小鼠对脂多糖诱导的发热以及响应于关键炎性细胞因子IL-1 β和TNF α的发热具有抗性。从机制上讲，RANKL激活参与体温调节的大脑区域，并通过COX 2-PGE（2）/EP 3R途径诱导发热。此外，雌性Nestin-Cre和GFAP-Cre等级（floxed）小鼠表现出基础体温升高，表明RANKL和RANK控制正常雌性生理过程中的体温调节。我们还发现两名RANK突变的儿童在肺炎期间表现出发热受损。这些数据确定了关键破骨细胞分化因子RANKL/RANK在女性体温调节和炎症中枢发热反应中的全新和意外功能。
Receptor-activator of NF-kappa B ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland(1-4). RANKL and RANK are also expressed in the central nervous system(5,6). However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1 beta and TNF alpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.