Hanada, ReikoLeibbrandt, AndreasHanada, ToshikatsuKitaoka, ShihoFuruyashiki, TomoyukiFujihara, HiroakiTrichereau, JeanPaolino, MagdalenaQadri, FatimunnisaPlehm, RalphKlaere, SteffenKomnenovic, VukoslavMimata, HiromitsuYoshimatsu, HironobuTakahashi, NaoyukiVon Haeseler, ArndtBader, MichaelUeta, YoichiPifl, ChristianNarumiya, ShuhPenninger, Josef M.2022-04-222022-04-222009-11-26Hanada, R. vd. (2009). "Central control of fever and female body temperature by RANKL/RANK". Nature, 462(7272), 505-509.0028-0836https://doi.org/10.1038/nature08596https://www.nature.com/articles/nature08596http://hdl.handle.net/11452/25990Receptor-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.eninfo:eu-repo/semantics/closedAccessOsteoclast differentiation factorFebrile responseMice lackingC-fosReceptorInflammationMechanismsDenosumabProteinLigandScience & technology - other topicsMusRattusBody temperatureBoneBrainFemaleLigandMutationPolysaccharideProteinRodentThermoregulationTumorAnimalsAstrocytesBody temperature regulationChildDinoprostoneFemaleFeverGene expression profilingHumansInjections, intraventricularMaleMiceMice, inbred C57BLPneumoniaRANK ligandRatsRats, wistarReceptor activator of nuclear factor-kappa BReceptors, prostaglandin ESex characteristicsArticle0002721442000442-s2.0-70849096810505509462727219940926Multidisciplinary sciencesOsteoprotegerin; Osteoclast Differentiation Factor; LigandsCre recombinaseCyclooxygenase 2Glial fibrillary acidic proteinInterleukin 1betaNestinOsteoclast differentiation factorProstaglandin E2Receptor activator of nuclear factor kappa BTumor necrosis factor alphaAnimal experimentAnimal modelArticleBody temperatureControlled studyEnzyme activationFemaleFeverGene mutationMouseNonhumanPneumoniaPriority journalProtein functionRatThermoregulation