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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Leibbrandt, A. & Penninger, J. M. RANK/RANKL: regulators of immune responses and bone physiology. Ann. NY Acad. Sci. 1143, 123–150 (2008)
Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999)
Cummings, S. R. et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 756–765 (2009)
Smith, M. R. et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N. Engl. J. Med. 361, 745–755 (2009)
Kartsogiannis, V. et al. Localization of RANKL (receptor activator of NFκ B ligand) mRNA and protein in skeletal and extraskeletal tissues. Bone 25, 525–534 (1999)
Nakagawa, N. et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem. Biophys. Res. Commun. 253, 395–400 (1998)
Dantzer, R. Cytokine-induced sickness behavior: mechanisms and implications. Ann. NY Acad. Sci. 933, 222–234 (2001)
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004)
Morrison, S. F., Nakamura, K. & Madden, C. J. Central control of thermogenesis in mammals. Exp. Physiol. 93, 773–797 (2008)
Sagar, S. M., Sharp, F. R. & Curran, T. Expression of c-fos protein in brain: metabolic mapping at the cellular level. Science 240, 1328–1331 (1988)
Elmquist, J. K., Scammell, T. E. & Saper, C. B. Mechanisms of CNS response to systemic immune challenge: the febrile response. Trends Neurosci. 20, 565–570 (1997)
Fleischmann, A. et al. Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS. J. Neurosci. 23, 9116–9122 (2003)
Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genet. 23, 99–103 (1999)
Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004 (2000)
Blatteis, C. M., Li, S., Li, Z., Feleder, C. & Perlik, V. Cytokines, PGE2 and endotoxic fever: a re-assessment. Prostaglandins Other Lipid Mediat. 76, 1–18 (2005)
McDermott, M. F. & Tschopp, J. From inflammasomes to fevers, crystals and hypertension: how basic research explains inflammatory diseases. Trends Mol. Med. 13, 381–388 (2007)
Ushikubi, F. et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 395, 281–284 (1998)
Fata, J. E. et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103, 41–50 (2000)
Guerrini, M. M. et al. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am. J. Hum. Genet. 83, 64–76 (2008)
Handschin, C. & Spiegelman, B. M. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature 454, 463–469 (2008)
Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008)
Isselbacher, K. J. et al. Harrison’s Principles of Internal Medicine 2, 13th edn 2021–2022 (McGraw-Hill, 1994)
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.
About this article
Cite this article
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
Proceedings of the Japan Academy, Series B (2020)
Journal of Cellular Physiology (2020)
Cell Reports (2020)
Scientific Reports (2020)
Journal of Bone and Mineral Metabolism (2020)