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Receptor-activator of NF-κB 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 gland1-4. RANKL and RANK are also expressed in the central nervous system5,6. 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^sup floxed^ deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank^sup floxed^ deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1β and TNFα. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE^sub 2^/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank^sup 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.
To test for a possible brain-specific function of the RANKL/RANK system, we performed stereotactic intracerebroventricular (i.c.v.) injections of recombinant RANKL into the lateral ventricle of rats (Supplementary Fig. 1a). Injection of RANKL did not alter serum alkaline phosphatase and serum Ca21 levels (Supplementary Fig. 1b), suggesting that central RANKL administration has no overt effects on osteoclasts. Within minutes after i.c.v. injection, RANKL administration resulted in markedly reduced activity of all animals tested. Further analyses revealed that RANKL i.c.v. injected rats developed very high fever (Fig. 1a, Supplementary Fig. 1c). Heat inactivation of RANKL abolished the fever response (Fig. 1b, Supplementary Fig. 1d), excluding possible endotoxin contaminations. Similar to rats, i.c.v. injections of RANKL into mouse brains triggered hyperthermia (Fig. 1c). As expected from a febrile response7, i.c.v. injections of RANKL also resulted in markedly reduced activity (Fig. 1d, Supplementary Fig. 2a). In vivo inhibition of RANKL with the natural decoy receptor osteoprotegerin alleviated the fever response in mice (Fig. 1e)...