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

Sepsis is an immune paradox where host defence is necessary for survival but also contributes to organ damage and death. Using lung intravital microscopy we defined an immunothrombosis cascade of neutrophil and platelets in the microcirculation in response to E. coli sepsis. Neutrophil cathelicidin localized neutrophils to E. coli and initiated founder immunothrombi via formyl-peptide receptors. Immunothrombi captured vascular bacteria and cathelicidin enabled antimicrobial activities in platelets. Blocking cathelicidin prevented the immunothrombosis cascade and attenuated early sepsis death but resulted in delayed death with uncontrolled infection. LTB4 amplified the immunothrombi and inhibiting it diminished detrimental immunothrombi 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 defence during sepsis.