title: Central control of fever and female body temperature by RANKL/RANK.
abstract: Receptor-activator of NF-kappaB 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 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-1beta and TNFalpha. 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.
authors: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
authors: Reiko
authors: R
authors: Hanada
authors: Andreas
authors: A
authors: Leibbrandt
authors: Toshikatsu
authors: T
authors: Hanada
authors: Shiho
authors: S
authors: Kitaoka
authors: Tomoyuki
authors: T
authors: Furuyashiki
authors: Hiroaki
authors: H
authors: Fujihara
authors: Jean
authors: J
authors: Trichereau
authors: Magdalena
authors: M
authors: Paolino
authors: Fatimunnisa
authors: F
authors: Qadri
authors: Ralph
authors: R
authors: Plehm
authors: Steffen
authors: S
authors: Klaere
authors: Vukoslav
authors: V
authors: Komnenovic
authors: Hiromitsu
authors: H
authors: Mimata
authors: Hironobu
authors: H
authors: Yoshimatsu
authors: Naoyuki
authors: N
authors: Takahashi
authors: Arndt
authors: A
authors: von Haeseler
authors: Michael
authors: M
authors: Bader
authors: Sara Sebnem
authors: SS
authors: Kilic
authors: Yoichi
authors: Y
authors: Ueta
authors: Christian
authors: C
authors: Pifl
authors: Shuh
authors: S
authors: Narumiya
authors: Josef M
authors: JM
authors: Penninger
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001833:Body Temperature Regulation / Q000187:drug effects* / Q000502:physiology*; D002648:Child; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D005334:Fever / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000150:complications / Q000378:metabolism; D053245:RANK Ligand / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype; D012727:Sex Characteristics
chemical_list: C545647:PTGER3 protein, human; C545648:Ptger3 protein, mouse; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D015232:Dinoprostone