Spontaneous and pharmacologically induced hypothermia protect mice against endotoxic shock

BACKGROUND AND PURPOSE: Despite the well-known occurrence of hypothermia during sepsis, its underlying biological nature and adaptive value remain debated. EXPERIMENTAL APPROACH: Using indirect calorimetry, telemetry, thermal gradient studies and pharmacological studies, we examined the thermal and metabolic responses of mice treated with a shock-inducing lethal dose of lipopolysaccharide (LPS). KEY RESULTS: We report that LPS-treated mice undergo spontaneous hypothermia, driven by hypometabolism and cold-seeking behaviours, even when animals approach the end of life. Conversely, rewarming LPS-treated mice at 30°C delayed hypothermia but worsened mortality, thus highlighting the adaptive importance of hypothermia. Additionally, we show that LPS-induced hypothermia was partly mediated by peripheral neurotensin expressed in response to vascular toll-like receptor 4 (TLR4) signalling. The administration of a neurotensin analogue (JMV449) induced pharmacological hypothermia and significantly ameliorated the clinical presentation and lethality rates in LPS-treated mice. Moreover, the therapeutic benefits of pharmacological hypothermia were prevented when LPS-treated mice were switched to 30°C. Lastly, these beneficial outcomes were attributed to a reduction in oxygen consumption, metabolic stress and cytopathic hypoxia, rather than the modulation of the cytokine storm. CONCLUSION AND IMPLICATIONS: Collectively, our findings indicate that spontaneous and pharmacologically-induced hypothermia protect against endotoxic shock.