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

• Published in: Nature (London) Vol. 462; no. 7272; pp. 505 - 509
• Main Authors: Ueta, Yoichi, Klaere, Steffen, Hanada, Reiko, Leibbrandt, Andreas, Bader, Michael, Trichereau, Jean, Paolino, Magdalena, Penninger, Josef M, Hanada, Toshikatsu, Kilic, Sara Sebnem, Pifl, Christian, Furuyashiki, Tomoyuki, Qadri, Fatimunnisa, von Haeseler, Arndt, Plehm, Ralph, Komnenovic, Vukoslav, Narumiya, Shuh, Fujihara, Hiroaki, Takahashi, Naoyuki, Kitaoka, Shiho, Mimata, Hiromitsu, Yoshimatsu, Hironobu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.11.2009; Nature Publishing Group
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - metabolism; Biological and medical sciences; Body temperature; Body Temperature Regulation - drug effects; Body Temperature Regulation - physiology; Brain; Central nervous system; Child; Control; Dinoprostone - metabolism; Female; Fever; Fever - chemically induced; Fever - complications; Fever - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Humanities and Social Sciences; Humans; Hyperthermia; Injections, Intraventricular; letter; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; multidisciplinary; Physiological aspects; Pneumonia - complications; Pneumonia - metabolism; Proteins; RANK Ligand - administration & dosage; RANK Ligand - antagonists & inhibitors; RANK Ligand - metabolism; RANK Ligand - pharmacology; Rats; Rats, Wistar; Receptor Activator of Nuclear Factor-kappa B - genetics; Receptor Activator of Nuclear Factor-kappa B - metabolism; Receptors, Prostaglandin E - metabolism; Receptors, Prostaglandin E, EP3 Subtype; Regulation; Rodents; Science; Science (multidisciplinary); Sex Characteristics; Tumor necrosis factor; Vertebrates: nervous system and sense organs; Lymph node; Rat; Neuroglia; Glial fibrillary acidic protein; Body temperature; Rodentia; Central nervous system; Astrocyte; Fever; Encephalon; Osteoarticular system; Vertebrata; Mammalia; Mouse; Tumor necrosis factor; Animal; Lipopolysaccharide; Female; Transcription factor NFκB; Bone; Biological receptor
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature08596

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 gland. RANKL and RANK are also expressed in the central nervous system. 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 rankfloxed deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rankfloxed deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1 and TNF . Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE2/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rankfloxed 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.