Thermoregulation RANKLed About Fevers?

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Perhaps best known for their role in regulating osteoclast differentiation, and thereby bone remodeling, receptor-activator of NF-B ligand (RANKL) and its receptor RANK have also been implicated in lymph node and mammary gland development. Noting that RANKL and RANK are also present in the central nervous system, Hanada et al. injected recombinant RANKL into the lateral cerebral ventricles of rats and mice and found that it elicited fevers, whereas intraperitoneal RANKL administration did not. Immunofluorescence analysis and in situ hybridization indicated that RANK and RANKL were present in brain regions involved in thermoregulation. Moreover, intracerebroventricular injection of RANKL elicited a functional response (increased c-Fos abundance and production of green fluorescent protein under the control of the c-Fos promoter) in regions of the brain implicated in the fever response. Intracerebroventricular injection of RANKL failed to provoke a fever or stimulate c-Fos accumulation in a line of mice that lacked RANK in brain, or in a line that specifically lacked RANK in astrocytes. Furthermore, intraperitoneal injection of lipopolysaccharide, or intraperitoneal or intracerebroventricular injection of the proinflammatory cytokines TNF- or IL-1β, elicited high fevers in wild-type mice but not in mice lacking brain or astrocytic RANK. Intracerebroventricular RANKL increased the abundance of cyclooxygenase 2 (COX2), and various lines of evidence indicated that the fever response to RANKL depended on COX2-dependent generation of prostaglandin E₂ (PGE₂) and PGE₂ signaling through the prostaglandin EP3 receptor. Notably, two children from a family with a homozygous RANK mutation showed an attenuated fever response during pneumonia infection. Intriguingly, female mice lacking brain or astrocyte RANK showed increased basal body temperature, and ovariectomy, which affected body temperature in wild-type mice but not in mice lacking brain RANK, led to a decrease in brain Rankl mRNA. The authors thus conclude that RANKL-RANK signaling plays a role in the fever response and in female thermoregulation and speculate that it may also mediate hot flashes in older women.

R. Hanada, A. Leibbrandt, T. Hanada, S. Kitaoka, T. Furuyashiki, H. Fujihara, J. Trichereau, M. Paolino, F. Qadri, R. Plehm, S. Klaere, V. Komnenovic, H. Mimata, H. Yoshimatsu, N. Takahashi, A. von Haeseler, M. Bader, S. S. Kilic, Y. Ueta, C. Pifl, S. Narumiya, J. M. Penninger, Central control of fever and female body temperature by RANKL/RANK. Nature 462, 505–509 (2009). [PubMed]

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