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

Abstract

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‑1β, tumor necrosis‑α 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.