Protective Effect of Melatonin Against Polymicrobial Sepsis Is Mediated by the Anti-bacterial Effect of Neutrophils

Area of Science:

• Immunology
• Endocrinology
• Pathology

Background:

• Sepsis is a life-threatening systemic inflammatory syndrome.
• Melatonin, a pineal hormone, shows protective effects against polymicrobial sepsis in animal models.
• The precise mechanisms underlying melatonin's anti-septic actions, particularly during polymicrobial infections, remain incompletely understood.

Purpose of the Study:

• To elucidate the protective mechanisms of melatonin in a mouse model of polymicrobial sepsis.
• To investigate the roles of macrophages and neutrophils in mediating melatonin's anti-septic effects.
• To determine whether melatonin enhances bacterial clearance via phagocytosis or neutrophil extracellular trap (NET) formation.

Main Methods:

• Utilized a cecal ligation and puncture (CLP) model to induce polymicrobial sepsis in mice.
• Administered melatonin and assessed its impact on inflammation, tissue damage, and mortality.
• Employed neutrophil and macrophage depletion strategies to evaluate their involvement in melatonin's protective effects.
• Analyzed neutrophil extracellular trap (NET) formation and phagocytic activity.

Main Results:

• Melatonin treatment significantly reduced peripheral tissue inflammation, tissue damage, and mortality in CLP-induced sepsis.
• Melatonin receptors were expressed on both macrophages and neutrophils.
• Neutrophil depletion abrogated melatonin's protective effects, while macrophage depletion did not.
• Melatonin promoted NET formation, enhancing anti-bacterial activity, but inhibited neutrophil phagocytosis.

Conclusions:

• Melatonin confers protection against polymicrobial sepsis primarily through neutrophil-mediated mechanisms, specifically by promoting NET formation.
• The anti-septic effect of melatonin is dependent on neutrophils but not significantly on macrophages.
• These findings provide a mechanistic basis for the previously observed antiseptic properties of melatonin and suggest its therapeutic potential in sepsis management.