[ODP-185/WS7-4] LL-37 ameliorates mouse sepsis by releasing antimicrobial extracellular vesicles
Extracellular vesicles (EV), such as exosomes and microvesicles (MV), secreted from host cells upon microbial infection modulate immune and infectious responses. Sepsis is a life-threatening multiple organ dysfunction caused by a systemic dysregulated inflammatory response to infection. We previously revealed that LL-37, a human cathelicidin host-defense peptide, improves the survival of septic mice. Here, we investigated the potential of LL-37 to secrete EV and functions of the EV in a murine sepsis model. In septic mice, the level of both exosomes and MV, especially neutrophil-derived MV, were enhanced by LL-37 administration. Interestingly, EV isolated from LL-37-injected septic mice contained higher amounts of neutrophil-derived antibacterial molecules and exhibited higher antibacterial activity compared to EV from PBS-injected septic mice. When exosomes and MV were partially separated by differential centrifugation, the antibacterial activity was mainly detected in MV fractions. Furthermore, LL-37 stimulated mouse bone marrow neutrophils to secret EV with antibacterial potential. Finally, administration of LL-37-induced EV reduced the bacterial load and improved the survival of septic mice. Taken together, LL-37 induces the secretion of antimicrobial EV from neutrophils in septic mice, thereby reducing the bacterial load and protecting mice from lethal septic conditions.