Visualizing a lung neutrophil-platelet immunothrombosis cascade during sepsis in mice

Sepsis is an immune paradox in which host defense is necessary for survival but also contributes to organ damage and death. We defined an immunothrombosis cascade of neutrophil and platelets in the lung microcirculation of Escherichia coli –septic mice. Cathelicidin, an antimicrobial peptide, localized neutrophils to E. coli and initiated immunothrombi through formyl-peptide receptors. Immunothrombi captured bacteria, and cathelicidin enabled antimicrobial activities in platelets. Blocking cathelicidin prevented immunothrombosis and attenuated early sepsis death but resulted in delayed death with uncontrolled infection. Leukotriene B4, an important neutrophil-to-neutrophil communication molecule, amplified immunothrombi, and inhibiting it improved vascular compromise while preserving host defense, thus representing a discrete inflection point of sepsis disease progression. Therefore, targeting the immunothrombi cascade can mitigate immunopathology without suppressing host defense during sepsis.