Thermoregulatory adjustments in sepsis: insights from the cecal ligation and puncture experimental model

Abstract Sepsis remains as a major health concern, given its high prevalence and mortality worldwide. Changes in body temperature (Tb), i.e., hypothermia or fever, are important diagnostic clues and part of the pathophysiology of this condition. Experimental studies often use bacterial lipopolysaccharide (LPS) to investigate the changes in Tb during sepsis, however, this model poorly mimics the complexity of this disease. In this work we aimed to characterize the thermoregulatory mechanisms during sepsis by using a clinically relevant murine model, the cecal ligation and puncture (CLP), and describe how sepsis severity and ambient temperature (Ta) modulate Tb regulation. We show that at thermoneutral Ta (28℃) the degree of the febrile response is proportional to the disease severity and the inflammatory response. In this condition, tail vasoconstriction, rather than non-shivering thermogenesis, seems to be the main generator of CLP-induced fever. On the other hand, when housed in a subthermoneutral Ta (22℃), animals are able to maintain Tb during mild sepsis, but develop a moderate hypothermia in a severe condition. This reduction in Tb was associated to lower UCP1 expression in the brown adipose tissue and less consistent tail vasoconstriction than the observed in mild sepsis. Although we observe differences in the thermoregulatory responses at the two Ta conditions, sepsis induced a persistent inflammatory response and increased the production of hypothalamic PGE2, a critical mediator of body temperature adjustments during an inflammatory condition. Mortality rate in response to severe sepsis was dramatically impacted by Ta (80% mortality at 28℃ and 0% mortality at 22℃). Our results demonstrate that the ambient temperature and the magnitude of the inflammatory insult deeply modulate the thermoregulatory responses and survival during sepsis.