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.

Cathelicidins: Immunomodulatory Antimicrobials

“…Nevertheless, the antimicrobial effects of cathelicidins must not completely be disregarded. In vivo they are readily incorporated into neutrophil extracellular traps (NETs), where they stabilize the NET and perhaps contribute to the antimicrobial function [ 51 , 52 ]. LL-37, along with other cationic peptides, has been shown to protect NETs from degradation by binding DNA in the NET and shielding it from bacterial nucleases [ 53 ].…”

Recent findings related to immune responses against leptospirosis and novel strategies to prevent infection

“…This study is important since it may open a new avenue to treat human leptospirosis. The recent finding that LL37 activates NET formation and reduces inflammation [68] may provide a potential mechanism for the observed protection of hamsters at the acute phase of infection, when both the bacterial load and inflammation are reaching their peak. BMAP, a bovine equivalent of LL37, has been shown to bind LPS and to decrease, in vitro, the leptospiral LPS induced signaling [31], which is important to elicit inflammation.…”

Memantine Displays Antimicrobial Activity by Enhancing Escherichia coli Pathogen-Induced Formation of Neutrophil Extracellular Traps

“…Notably, NETs have been shown to be an important antibacterial mechanism, since NETs can capture microbial pathogens and exert bactericidal activity through the action of antimicrobial peptides, histone and other NET-associated components (Hosoda et al, 2017). Our laboratory has demonstrated that α7R is an essential regulator of the host inflammatory response against bacteria (Chi et al, 2011).…”

“…Polymorphonuclear neutrophils (PMNs), the most abundant leukocytes in humans and other primates, play a central role in innate host defense against invading microorganisms (Hosoda et al, 2017). Activation of reactive oxygen species (ROS) is an important mechanism by which PMNs kill bacteria (Nguyen et al, 2017).…”