Low body temperature governs the decline of circulating lymphocytes during hibernation through sphingosine-1-phosphate

Hjalmar R. Bouma*, Frans G. M. Kroese, Jan Willem Kok, Fatimeh Talaei, Ate S. Boerema, Annika Herwig, Oana Draghiciu, Azuwerus van Buiten, Anne H. Epema, Annie van Dam, Arjen M. Strijkstra, Robert H. Henning

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

75 Citations (Scopus)


Hibernation is an energy-conserving behavior consisting of periods of inhibited metabolism ('torpor') with lowered body temperature. Torpor bouts are interspersed by arousal periods, in which metabolism increases and body temperature returns to euthermia. In deep torpor, the body temperature typically decreases to 2-10 degrees C, and major physiological and immunological changes occur. One of these alterations constitutes an almost complete depletion of circulating lymphocytes that is reversed rapidly upon arousal. Here we show that torpor induces the storage of lymphocytes in secondary lymphoid organs in response to a temperature-dependent drop in plasma levels of sphingosine-1-phosphate (S1P). Regulation of lymphocyte numbers was mediated through the type 1 S1P receptor (S1P(1)), because administration of a specific antagonist (W146) during torpor (in a Syrian hamster at similar to 8 degrees C) precluded restoration of lymphocyte numbers upon subsequent arousal. Furthermore, S1P release from erythrocytes via ATP-binding cassette (ABC)-transporters was significantly inhibited at low body temperature (4 degrees C) but was restored upon rewarming. Reversible lymphopenia also was observed during daily torpor (in a Djungarian hamster at +/- 25 degrees C), during forced hypothermia in anesthetized (summer-active) hamsters (at +/- 9 degrees C), and in a nonhibernator (rat at similar to 19 degrees C). Our results demonstrate that lymphopenia during hibernation in small mammals is driven by body temperature, via altered plasma S1P levels. S1P is recognized as an important bioactive lipid involved in regulating several other physiological processes as well and may be an important factor regulating additional physiological processes in hibernation as well as in mediating the effects of therapeutic hypothermia in patients.

Original languageEnglish
Pages (from-to)2052-2057
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number5
Publication statusPublished - 1-Feb-2011


  • immunology
  • anesthesiology
  • sphingolipid
  • inflammation
  • suspended animation


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