title: Antimicrobial cathelicidin peptide LL-37 inhibits the pyroptosis of macrophages and improves the survival of polybacterial septic mice.
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 can modulate various inflammatory reactions. We previously revealed that LL-37 suppresses the LPS/ATP-induced pyroptosis of macrophages in vitro by both neutralizing the action of LPS and inhibiting the response of P2X7 (a nucleotide receptor) to ATP. Thus, in this study, we further evaluated the effect of LL-37 on pyroptosis in vivo using a cecal ligation and puncture (CLP) sepsis model. As a result, the intravenous administration of LL-37 improved the survival of the CLP septic mice. Interestingly, LL-37 inhibited the CLP-induced caspase-1 activation and pyroptosis of peritoneal macrophages. Moreover, LL-37 modulated the levels of inflammatory cytokines (IL-1β, IL-6 and TNF-α) in both peritoneal fluids and sera, and suppressed the activation of peritoneal macrophages (as evidenced by the increase in the intracellular levels of IL-1β, IL-6 and TNF-α). Finally, LL-37 reduced the bacterial burdens in both peritoneal fluids and blood samples. Together, these observations suggest that LL-37 improves the survival of CLP septic mice by possibly suppressing the pyroptosis of macrophages, and inflammatory cytokine production by activated macrophages and bacterial growth. Thus, the present findings imply that LL-37 can be a promising candidate for sepsis because of its many functions, such as the inhibition of pyroptosis, modulation of inflammatory cytokine production and antimicrobial activity.
authors.affiliation: Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Zhongshuang
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan Laboratory Program Support (LPS) Consulting Office, Tokyo 160-0023, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tamura
authors.affiliation: Institute of Physical and Theoretical Chemistry, University of Regensburg 93040, Regensburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Reich
authors.affiliation: Department of Bacteriology, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kuwahara-Arai
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Iba
authors.affiliation: Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan nagaokai@juntendo.ac.jp.
authors.forename: Isao
authors.initials: I
authors.lastname: Nagaoka
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D016207:Cytokines; D008070:Lipopolysaccharides; D054804:Cathelicidins
keywords: IL-1β; caspase-1; cecal ligation and puncture; cytokines; sepsis