Abstract
Sepsis is an infection- or toxin-mediated systemic inflammatory syndrome. Previous studies have shown that melatonin, the primary hormone produced by the pineal gland, attenuates the effect of polymicrobial infection-mediated septic shock in animals. However, the mechanism of the anti-septic effect of melatonin during polymicrobial infection has not been well-studied. In this study, we investigated how melatonin protects mice from polymicrobial sepsis. Melatonin treatment inhibited peripheral tissue inflammation and tissue damage in a cecal ligation puncture (CLP)-induced polymicrobial sepsis model, consequently reducing the mortality of the mice. We found that macrophages and neutrophils expressed melatonin receptors. Upon depletion of neutrophils, melatonin-induced protection against polymicrobial infection failed in the mice, but melatonin treatment in macrophage-depleted mice attenuated the mice mortality resulting from polymicrobial sepsis. Moreover, melatonin treatment promoted the development of the neutrophil extracellular trap (NET), which contributed to anti-bacterial activity during polymicrobial infection, whereas the phagocytic activities of neutrophils were inhibited by melatonin. The data from this study support previously unexplained antiseptic effects of melatonin during a polymicrobial infection and could be potentially useful for human patients with sepsis.
Highlights
Sepsis is a systemic inflammatory response syndrome caused by an infection, which can lead to multiple organ dysfunction and mortality
The cecal ligation puncture (CLP) surgery induced an increase in the number of bacterial colony forming units (CFUs) in the lung, liver, and spleen tissues, as well as in the peritoneal and bronchoalveolar lavage fluids (BALF), while melatonin treatment dramatically reduced the bacterial CFUs in these tissues and fluids (Figures 1B,C)
We examined peripheral tissue failure and found that CLP surgery promoted an increase in the lung wet/dry ratio, indicating the development of pulmonary edema, while melatonin treatment inhibited the increase in the lung wet/dry ratio (Supplementary Figure 1A)
Summary
Sepsis is a systemic inflammatory response syndrome caused by an infection, which can lead to multiple organ dysfunction and mortality. Sepsis as an acute response to a pathogen or its toxin in the early stage promotes the elevation of pro-inflammatory cytokine levels, known as cytokine storm, leading to high fever, tachycardia, and tachypnea [2]. Overexpression of pro-inflammatory cytokines is required for the clearance of the invading pathogens, they contribute to tissue inflammation and multi-organ dysfunction [2,3,4]. To prevent a septic cytokine storm, anti-inflammatory reagents have been used in patients [5, 6]. Treatment with anti-inflammatory reagents typically fails to recover the sepsis, as they inhibit
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