Central control of fever and female body temperature by RANKL/RANK.
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.
Hanada
Reiko
R
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.
Leibbrandt
Andreas
A
Hanada
Toshikatsu
T
Kitaoka
Shiho
S
Furuyashiki
Tomoyuki
T
Fujihara
Hiroaki
H
Trichereau
Jean
J
Paolino
Magdalena
M
Qadri
Fatimunnisa
F
Plehm
Ralph
R
Klaere
Steffen
S
Komnenovic
Vukoslav
V
Mimata
Hiromitsu
H
Yoshimatsu
Hironobu
H
Takahashi
Naoyuki
N
von Haeseler
Arndt
A
Bader
Michael
M
Kilic
Sara Sebnem
SS
Ueta
Yoichi
Y
Pifl
Christian
C
Narumiya
Shuh
S
Penninger
Josef M
JM
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
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