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

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Abstract

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 gland1,2,3,4. 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 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-1β and TNFα. 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.

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Figure 1: RANKL/RANK control fever in the central nervous system.
Figure 2: Central RANK mediates the inflammatory fever response.
Figure 3: RANKL induces PGE 2 and mediates fever via the EP3R.
Figure 4: RANK controls thermoregulation in female mice and fever in children with RANK mutations.

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Acknowledgements

We thank C. Xia, A. Muto, T. Mizoguchi, T. Katakai, T. Mitsumori, D. Sakata, T. Matsuoka, I. Williams, M. Iehara, T. Katafuchi, K. Matsuo, J. Wojciechowski, C. Theussl, T. Nakashima, T. Wada and R. Koglgruber for their assistance and all members of our laboratory for discussions. We thank E. Wagner for the c-Fos–GFP reporter mice and M. Kopf for the IL-1Rα mutant mice. This work was in part supported by UEHARA Foundation and Japan Foundation for Applied Enzymology grants. S.K. and A.v.H. are supported by the Austrian Ministry for Science and Research (GEN-AU Bioinformatics Integration Network II) and the Wiener Wissenschafts-, Forschungs- und Technologiefonds (WWTF). J.M.P. is supported by grants from IMBA, the Austrian Ministry of Sciences, the Austrian Academy of Sciences, GEN-AU (AustroMouse), an EU Marie Curie Excellence Grant, and an EU ERC Advanced Grant.

Author Contributions R.H. carried out the experiments with help from T.H. A.L. generated rankfloxed mice. S.K. and A.v.H. provided professional biostatistics support for data analysis. V.K. helped with immunostaining. H.M. and H.Y. provided key reagents and technical help for i.c.v. injections. H.F. and Y.U. performed RANKL in situ hybridizations. J.T. and M.P. helped in cytokine enzyme-linked immunosorbent assays (ELISAs) and UCP1 expression. N.T. developed the reproducible RANK staining protocol in his laboratory. S.K., T.F. and S.N. provided EP3R mutant mice and established the perfusion of the brain slice and quantification of PGE2 procedure. F.Q., R.P. and M.B. performed rat telemetry experiments. S.S.K. is the clinician of the two RANK mutant children and provided their fever data. C.P. helped with rat experiments. J.M.P. coordinated the project, wrote the manuscript, and together with R.H. designed the experiments.

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Correspondence to Josef M. Penninger.

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Hanada, R., Leibbrandt, A., Hanada, T. et al. Central control of fever and female body temperature by RANKL/RANK. Nature 462, 505–509 (2009) doi:10.1038/nature08596

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