Central control of fever and female body temperature by RANKL/RANK (original) (raw)

Nature volume 462, pages 505–509 (2009)Cite this article

Abstract

Receptor-activator of NF-_κ_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 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 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-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 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.

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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 rank floxed 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.

Author information

Authors and Affiliations

  1. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
    Reiko Hanada, Andreas Leibbrandt, Toshikatsu Hanada, Jean Trichereau, Magdalena Paolino, Vukoslav Komnenovic & Josef M. Penninger
  2. Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
    Shiho Kitaoka, Tomoyuki Furuyashiki & Shuh Narumiya
  3. Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan
    Hiroaki Fujihara & Yoichi Ueta
  4. Max Delbrueck Centre for Molecular Medicine, 13125 Berlin, Germany
    Fatimunnisa Qadri, Ralph Plehm & Michael Bader
  5. Center of Integrated Bioinformatics, Max F. Perutz Laboratories, 1030 Vienna, Austria
    Steffen Klaere & Arndt von Haeseler
  6. Oita University Faculty of Medicine, Oita 879-5593, Japan
    Hiromitsu Mimata & Hironobu Yoshimatsu
  7. Institute for Oral Science, Matsumoto Dental University, Nagano 399-0781, Japan
    Naoyuki Takahashi
  8. Uludag University Medical Faculty, 16059 Bursa, Turkey
    Sara Sebnem Kilic
  9. Medical University of Vienna, Center for Brain Research, 1090 Vienna, Austria
    Christian Pifl

Authors

  1. Reiko Hanada
  2. Andreas Leibbrandt
  3. Toshikatsu Hanada
  4. Shiho Kitaoka
  5. Tomoyuki Furuyashiki
  6. Hiroaki Fujihara
  7. Jean Trichereau
  8. Magdalena Paolino
  9. Fatimunnisa Qadri
  10. Ralph Plehm
  11. Steffen Klaere
  12. Vukoslav Komnenovic
  13. Hiromitsu Mimata
  14. Hironobu Yoshimatsu
  15. Naoyuki Takahashi
  16. Arndt von Haeseler
  17. Michael Bader
  18. Sara Sebnem Kilic
  19. Yoichi Ueta
  20. Christian Pifl
  21. Shuh Narumiya
  22. Josef M. Penninger

Corresponding author

Correspondence toJosef 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). https://doi.org/10.1038/nature08596

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Editorial Summary

The protein RANK (receptor-activator of nuclear factor κB) and its ligand RANKL are essential bone marrow regulators, and antibodies against RANKL are being developed as therapeutics in osteoporosis. RANKL and RANK are also expressed in the central nervous system, though their function there has been unclear. Studies in rats and mice now show that RANKL/RANK are expressed in astrocytes in the brain and that surprisingly, animals injected with RANKL develop severe fever, whereas genetically engineered mice with astrocytes lacking RANK are fever-resistant. Other data are consistent with a role for RANKL/RANK in both the central fever response in inflammation and in the control of female body temperature. Interestingly, clinical observations of two children with osteoporosis associated with RANK mutations revealed an absence of fever during bouts of pneumonia. It is possible that RANKL/RANK are factors in the hot flashes or flushes sometimes experienced by women during the menopause.