Abstract
Sepsis is caused by a dysregulated host response to infection, and characterized by uncontrolled inflammation together with immunosuppression, impaired innate immune functions of phagocytes and complement activation. Septic patients develop fever or hypothermia, being the last one characteristic of severe cases. Both lipopolysaccharide (LPS) and Tumor Necrosis Factor (TNF)-α- induced septic shock in mice is dependent on the time of administration. In this study, we aimed to further characterize the circadian response to high doses of LPS. First, we found that mice injected with LPS at ZT11 developed a higher hypothermia than those inoculated at ZT19. This response was accompanied by higher neuronal activation of the preoptic, suprachiasmatic, and paraventricular nuclei of the hypothalamus. However, LPS-induced Tnf-α and Tnf-α type 1 receptor (TNFR1) expression in the preoptic area was time-independent. We also analyzed peritoneal and spleen macrophages, and observed an exacerbated response after ZT11 stimulation. The serum of mice inoculated with LPS at ZT11 induced deeper hypothermia in naïve animals than the one coming from ZT19-inoculated mice, related to higher TNF-α serum levels during the day. We also analyzed the response in TNFR1-deficient mice, and found that both the daily difference in the mortality rate, the hypothermic response and neuronal activation were lost. Moreover, mice subjected to circadian desynchronization showed no differences in the mortality rate throughout the day, and developed lower minimum temperatures than mice under light-dark conditions. Also, those injected at ZT11 showed increased levels of TNF-α in serum compared to standard light conditions. These results suggest a circadian dependency of the central thermoregulatory and peripheral inflammatory response to septic-shock, with TNF-α playing a central role in this circadian response.
Highlights
Sepsis is a syndrome characterized by a dysregulated host response to a pathogen and is the primary cause of death from infection (Singer et al, 2016)
We analyzed the minimum temperature attained by each animal and found that those injected at ZT11 showed a lower minimum temperature than those stimulated at ZT19 (Figure 1D; p < 0.0001)
When we analyzed the small peritoneal macrophages (SPMs) subset, we found that there was no alteration in cell percentage due to the treatment, but there was a daily variation of the basal percentages, showing higher levels at ZT11 compared to ZT19 (Figure 4E; p = 0.0346)
Summary
Sepsis is a syndrome characterized by a dysregulated host response to a pathogen and is the primary cause of death from infection (Singer et al, 2016). In the United States, the incidence of severe sepsis is more than 3 per 1,000 persons (Kumar et al, 2011) and the in-hospital mortality rate is about 25–30% of septic patients worldwide (Vincent et al, 2014) Septic shock is defined as the septic condition worsened by metabolic and circulatory alterations, as hypotension, which increase the mortality rate (Singer et al, 2016). As it is a complex and multi-symptomatic pathology, it may be important to differentiate between those symptoms related with more severe cases from those compatible with a better prognosis. The hypothalamic preoptic area (POA) is the main integrative brain site for thermoregulation, controlling brain and peripheral body temperature (Boulant, 1998; Morrison and Nakamura, 2018)
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