Disordered peptides impair neutrophil bacterial clearance and enhance tissue damage in septic patients

Neutrophilic granulocytes are required for antimicrobial defense, but they can also be harmful to the host organism. The current study demonstrates that disordered peptides in the 3-12 kDa size range in the plasma of septic patients alter effector functions of neutrophils from healthy donors. Those peptides stimulated exocytosis, increased extracellular release of reactive oxygen species (ROS), decreased ROS production in phagosomes, and impaired elimination of ROS-sensitive bacteria. Both the concentration of peptides in patients plasma and their effects on healthy cells were proportional to the clinical status of the patients. Proteomic analysis and in silico modeling indicate that multiple proteases generate the toxic peptides, with the greatest number of peptides cleaved by neutrophil elastase. We propose that neutrophils participate in an amplification loop in which proteolytic peptides stimulate extracellular release of proteases, resulting in production of more peptides. The enhanced extracellular ROS release contributes to tissue damage, while reduced intracellular ROS generation impairs elimination of certain bacteria. Breaking of this vicious cycle may offer a potential target for intervention.