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.

The Human LL-37(17-29) Antimicrobial Peptide Reveals a Functional Supramolecular Nanostructure

“…Human LL-37 (hLL-37) AMP, a hCAP-18 protein cleavage product, is also known to form fibrils (20). LL-37 is expressed by various mammalian cells and is considered to play an important role in the first line of defense against pathogens (21)(22)(23)(24)(25)(26). Fibrillation of LL-37 was found critical for binding DNA and affecting receptors in the immune system (27).…”

The Effects of the Human Host Defense Peptide LL-37 on Endothelial Cells

“…However during our study, we unexpectedly found that LL-37 enhances the LPS uptake by liver sinusoidal endothelial cells (LSECs) through the complex formation with LPS without activation of TLR4 signaling. This result suggests that the LL-37-mediated cargo delivery is functioning to inhibit the host cell responses in endothelial cells 12) .…”

“…Thus, LL-37 enhances the uptake of LPS and promotes the LPS clearance and degradation by LSECs without cell activation (Figure-5). It should be clarified in the future whether LL-37 promotes LPS clearance in vivo via the enhancement of LPS uptake by LSECs 12) .…”

“…The right panel shows an LL-37-induced clearance of LPS by endothelial cells (LPS clearance). The complexes of LL-37 and LPS are incorporated into LSECs without cell activation, and translocated to lysosomes for degradation 12) . Thus, LL-37 protects endothelial cells from the action of LPS by dual mechanism (inhibition of the LPS-binding to the cells and clearance of LPS by the cells).…”

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

“…Recent reports indicate that some cancer cells have cholesterol-rich lipid rafts, which could also be a key factor governing LL-37 selectivity for different cancer cells, thus providing a novel possibility besides the anti-cancer mechanisms of LL-37 already mentioned [1,5,93,94]. 5) [90].…”