Super-low dose endotoxin pre-conditioning exacerbates sepsis mortality

Area of Science:

• Immunology
• Infectious Disease
• Sepsis Pathophysiology

Background:

• Sepsis mortality exhibits significant variability linked to immune status, with underlying mechanisms poorly understood.
• Innate immunity may possess rudimentary memory, evidenced by endotoxin priming and tolerance in vitro.
• Prior in vivo studies focused solely on the protective effects of endotoxin tolerance in sepsis.

Purpose of the Study:

• To investigate the contrasting effects of super-low versus low-dose endotoxin lipopolysaccharide (LPS) pre-conditioning on sepsis survival.
• To elucidate the underlying mechanisms, specifically the role of neutrophil extracellular trap (NET) formation.

Main Methods:

• Murine model of sepsis induced by cecal-ligation and puncture (CLP).
• Pre-conditioning of mice with either super-low or low doses of LPS.
• Assessment of survival rates, tissue damage, inflammation, bacterial load, and neutrophil extracellular trap (NET) formation.
• Analysis of extracellular signal-regulated kinase (ERK) activation in neutrophils.

Main Results:

• Super-low dose LPS pre-conditioning led to increased mortality, severe tissue damage, heightened inflammation, and elevated bacterial load in CLP mice.
• Low dose LPS pre-conditioning demonstrated protective effects against sepsis, consistent with previous findings.
• Super-low LPS dose significantly reduced ERK activation and compromised NET generation in neutrophils, contrasting with low-dose LPS effects.

Conclusions:

• Super-low and low doses of LPS differentially modulate innate immune responses, leading to opposite sepsis survival outcomes.
• Compromised neutrophil extracellular trap (NET) formation due to reduced ERK activation is a key mechanism underlying the detrimental effects of super-low dose LPS.
• These findings reveal a novel mechanism for dynamic programming of innate immunity in vivo concerning sepsis risk.