[WS7] Selected from Oral Session: Virulence Factors and Biophylaxis: Toxins, Effectors, Bioactive substances

[WS7-4/ODP-185] LL-37 ameliorates mouse sepsis by releasing antimicrobial extracellular vesicles

○Yumi Kumagai¹, Soichiro Kakuta², Kyoko Kuwahara³, Isao Nagaoka^1,4 (¹Dept. Host Defense Biochem. Res., Sch. Med., Juntendo Univ., ²Lab. Morphol. Image Analysis, Sch. Med., Juntendo Univ., ³Dept. Microbiol., Sch. Med., Juntendo Univ., ⁴Faculty Health Sci., Juntendo Univ.)

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.