Central control of fever and female body temperature by RANKL/RANK

Date

2009-11-26

Authors

Hanada, Reiko
Leibbrandt, Andreas
Hanada, Toshikatsu
Kitaoka, Shiho
Furuyashiki, Tomoyuki
Fujihara, Hiroaki
Trichereau, Jean
Paolino, Magdalena
Qadri, Fatimunnisa
Plehm, Ralph

Journal Title

Journal ISSN

Volume Title

Publisher

Nature Research

Abstract

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.

Description

Keywords

Osteoclast differentiation factor, Febrile response, Mice lacking, C-fos, Receptor, Inflammation, Mechanisms, Denosumab, Protein, Ligand, Science & technology - other topics, Mus, Rattus, Body temperature, Bone, Brain, Female, Ligand, Mutation, Polysaccharide, Protein, Rodent, Thermoregulation, Tumor

Citation

Hanada, R. vd. (2009). "Central control of fever and female body temperature by RANKL/RANK". Nature, 462(7272), 505-509.

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