title: Human Host Defense Cathelicidin Peptide LL-37 Enhances the Lipopolysaccharide Uptake by Liver Sinusoidal Endothelial Cells without Cell Activation.
abstract: The liver is a major organ that removes waste substances from the blood, and liver sinusoidal endothelial cells (LSECs) are professional scavenger cells, which incorporate and degrade various endogenous and exogenous molecules including pathogenic factor LPS. Mammalian cells express a number of peptide antibiotics that function as effectors in the innate host defense systems. LL-37, a human cathelicidin antimicrobial peptide, has a potent LPS-neutralizing activity and exhibits protective actions on various infection models. However, the effect of LL-37 on the LPS clearance has not been clarified. In this study, to further understand the host-protective mechanism of LL-37, we evaluated the effect of LL-37 on the LPS clearance in vitro. LL-37 enhanced the LPS uptake by human LSECs. Of interest, LL-37 was similarly incorporated into LSECs both in the presence and the absence of LPS, and the incorporated LPS and LL-37 were colocalized in LSECs. Importantly, the uptake of LPS and LL-37 was inhibited by endocytosis inhibitors, heparan sulfate proteoglycan analogs, and glycosaminoglycan lyase treatment of the cells. Moreover, the uptake of LL-37-LPS did not activate TLR4 signaling in both MyD88-dependent and -independent pathways. In addition, the incorporated LL-37-LPS was likely transported to the lysosomes in LSECs. Together these observations suggest that LL-37 enhances the LPS uptake by LSECs via endocytosis through the complex formation with LPS and the interaction with cell-surface heparan sulfate proteoglycans, thereby facilitating the intracellular incorporation and degradation of LPS without cell activation. In this article, we propose a novel function of LL-37 in enhancing LPS clearance.
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;
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: 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; Laboratory Program Support Consulting Office, Tokyo 160-0023, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tamura
authors.affiliation: Department of Bacteriology, Juntendo University, Graduate School of Medicine, Tokyo 113-8421, Japan; and.
authors.forename: Kyoko
authors.identifier: http://orcid.org/0000-0003-4642-5146
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.identifier: http://orcid.org/0000-0003-0824-7406
authors.initials: I
authors.lastname: Nagaoka
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000276:immunology*; D001692:Biological Transport / Q000276:immunology; D015153:Blotting, Western; D042783:Endothelial Cells / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology*; D008099:Liver / Q000276:immunology*; D012157:Mononuclear Phagocyte System / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D008070:Lipopolysaccharides; D054804:Cathelicidins