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

Abstract

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°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 ∼8°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°C) but was restored upon rewarming. Reversible lymphopenia also was observed during daily torpor (in a Djungarian hamster at ± 25°C), during forced hypothermia in anesthetized (summer-active) hamsters (at ± 9°C), and in a nonhibernator (rat at ∼19°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.ibernation is an energy-conserving behavior consisting of periods of significantly inhibited metabolism (torpor) that result in a largely reduced heart and ventilation rate (1-3) and body temperature. Torpor bouts are interspersed by arousal periods with durations of 8-24 h, during which metabolism increases and body temperature rapidly returns to euthermia (2, 4). Hibernating mammals display major changes in their physiology that lead (among other changes) to an increased resistance to ischemia/reperfusion (5, 6) and a reduced immune function (7). Remarkably, despite the repetitive cycles of cooling and rewarming, hibernating animals do not show gross signs of organ damage (8). In humans, therapeutic hypothermia is used frequently to limit neuronal injury in cardiac arrest and major surgery of brain and heart (9). However, hypothermia as used during cardiac surgery is associated with increased renal injury postoperatively (10). Therefore, unraveling the mechanisms underlying the changes in physiology of hibernating mammals might be of substantial clinical relevance.

The role of endogenous H2S formation in reversible remodeling of lung tissue during hibernation in the Syrian hamster

“…We found only minor signs of immune activation, consistent with suppression of the immune function occurring in torpor (Bouma et al, 2011). We did observe substantial changes in ECM composition and the inhibition of MMP activity during torpor.…”

“…We found no significant change in the CD45 expression in lungs throughout the hibernating phases. Thus, it is reasonable to assume that extravasation of leukocytes into the lung tissue is absent during arousal, notwithstanding the presence of normal numbers of circulating leukocytes (Bouma et al, 2011). In accord, expression of NF-B (P65), ICAM-1 and VCAM-1 normalized to euthermic levels during arousal, which may prevent excess adhesion and infiltration of immune cells into the tissue in arousal.…”

“…Therefore, the changes in MMP activity may well underlie the lung remodeling as observed in hibernation, and these changes are probably related to low temperatures. Indeed, previous analyses of striated muscle, brain and circulating immune cells represent cases in which changes are specific to hibernation or driven by lowered body temperature (Bouma et al, 2011;Nowell et al, 2011;von der Ohe et al, 2006).…”

Long-term High-Soybean Oil Feeding Alters Regulation of Body Temperature in Rats

“…7,9) Anandamide and sphingosine-1-phosphate led to increased BT following central injection. 13,42) To date, no adipokines or lipid mediators have been shown to produce hypothermia. In contrast, there are several reports that FAs can influence membrane fluidity or characteristics of receptors/ion channels in the cell mem- brane.…”

“…Most of these mediators have receptors/ binding proteins and are integrated into intracellular signaling pathways in the CNS. 7,[10][11][12][13] In addition, fatty acids (FA) and cholesterol are important components of membranes of cell, synaptic vesicles and mitochondria, and are responsible for the characteristics of membranes. The FA composition in the CNS can also be changed by fat intake.…”