Antimicrobial cathelicidin peptide LL-37 induces NET formation and suppresses the inflammatory response in a mouse septic model

LL-37 is the only known member of the cathelicidin family of antimicrobial peptides in humans. In addition to its broad spectrum of antimicrobial activities, LL-37 may modulate various inflammatory reactions. The authors previously revealed that LL-37 improves the survival of a murine cecal ligation and puncture (CLP) sepsis model. In the present study, the mechanism for the protective action of LL-37 was elucidated using the CLP model, focusing on the effect of LL-37 on the release of neutrophil extracellular traps (NETs). The results indicated that the intravenous administration of LL-37 suppressed the increase of damage-associated molecular patterns (DAMPs), including histone-DNA complex and high-mobility group protein 1, in addition to interleukin-1 beta, tumor necrosis-alpha and soluble triggering receptor expressed on myeloid cells (TREM)-1 in plasma and peritoneal fluids. Notably, LL-37 significantly suppressed the decrease of mononuclear cell number in blood, and the increase of polymorphonuclear cell (neutrophil) number in the peritoneal cavity during sepsis. Furthermore, LL-37 reduced the bacterial burden in blood and peritoneal fluids. Notably, LL-37 increased the level of NETs (myeloperoxidase-DNA complex) in plasma and peritoneal fluids. In addition, it was verified that LL-37 induces the release of NETs from neutrophils, and NETs possess the bactericidal activity. Overall, these observations suggest that LL-37 improves the survival of CLP septic mice by possibly suppressing the inflammatory responses as evidenced by the inhibition of the increase of cytokines, soluble TREM-1 and DAMPs (host cell death) and the alteration of inflammatory cell numbers, and bacterial growth via the release of NETs with bactericidal activity.