Spontaneous and pharmacologically induced hypothermia protect mice against endotoxic shock

Abstract

Background and PurposeDespite the well‐known occurrence of hypothermia during sepsis, its underlying biological nature and adaptive value remain debated.Experimental ApproachUsing 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 ResultsWe 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 ImplicationsCollectively, our findings indicate that spontaneous and pharmacologically‐induced hypothermia protect against endotoxic shock.