The scavenger endothelial cell: a new player in homeostasis and immunity

Sørensen, Karen Kristine; McCourt, Peter; Berg, Trond; Crossley, Clive; Couteur, David G. Le; Wake, Kanako; Smedsrød, Bård

doi:10.1152/ajpregu.00686.2011

Cited by 189 publications

(241 citation statements)

References 170 publications

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“…It is generally accepted that extracellular macromolecules, as well as entire cells, are turned over by uptake and lysosomal degradation in specialized scavenger cells, namely, macrophages and scavenger endothelial cells (SECs). 35 Functionally, macrophages represent the professional phagocyte responsible for the elimination of larger particles. 35 While clearance of the BsAbs via resident liver macrophages was plausible, the lack of effect of macrophage depletion on clearance (Fig.…”

Section: Discussionmentioning

confidence: 99%

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Datta‐Mannan

Croy

Schirtzinger

et al. 2016

mAbs

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(2016) Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys, mAbs, 8:5, 969-982, DOI: 10.1080/19420862.2016 To link to this article: https://doi.org/10. 1080/19420862.2016 ABSTRACT Bispecific antibodies (BsAbs) can affect multiple disease pathways, thus these types of constructs potentially provide promising approaches to improve efficacy in complex disease indications. The specific and non-specific clearance mechanisms/biology that affect monoclonal antibody (mAb) pharmacokinetics are likely involved in the disposition of BsAbs. Despite these similarities, there are a paucity of studies on the in vivo biology that influences the biodistribution and pharmacokinetics of BsAbs. The present case study evaluated the in vivo disposition of 2 IgG-fusion BsAb formats deemed IgG-ECD (extracellular domain) and IgG-scFv (single-chain Fv) in cynomolgus monkeys. These BsAb molecules displayed inferior in vivo pharmacokinetic properties, including a rapid clearance (> 0.5 mL/hr/kg) and short half-life relative to their mAb counterparts. The current work evaluated factors in vivo that result in the aberrant clearance of these BsAb constructs. Results showed the rapid clearance of the BsAbs that was not attributable to target binding, reduced neonatal Fc receptor (FcRn) interactions or poor molecular/biochemical properties. Evaluation of the cellular distribution of the constructs suggested that the major clearance mechanism was linked to binding/association with liver sinusoidal endothelial cells (LSECs) versus liver macrophages. The role of LSECs in facilitating the clearance of the IgG-ECD and IgG-scFv BsAb constructs described in these studies was consistent with the minimal influence of clodronate-mediated macrophage depletion on the pharmacokinetics of the constructs in cynomolgus monkeys The findings in this report are an important demonstration that the elucidation of clearance mechanisms for some IgG-ECD and IgGscFv BsAb molecules can be unique and complicated, and may require increased attention due to the proliferation of these more complex mAb-like structures.

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Section: Discussionmentioning

confidence: 99%

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Datta‐Mannan

Croy

Schirtzinger

et al. 2016

mAbs

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“…Noteworthy, HSPGs are required for the initial recruitment of Tat onto the cell surface, and a scavenger receptor low-density lipoprotein receptor-related protein is responsible for the exact uptake of Tat (53). Importantly, LL-37 is recognized as a CPP (36), and LSECs express various scavenger receptors (54). Thus, it is reasonable to speculate that the LL-37-LPS complex initially interacts with cell-surface HSPGs and subsequently binds with some scavenger receptor(s) on LSECs for the incorporation.…”

Section: Discussionmentioning

confidence: 99%

Human Host Defense Cathelicidin Peptide LL-37 Enhances the Lipopolysaccharide Uptake by Liver Sinusoidal Endothelial Cells without Cell Activation

Suzuki

Murakami

et al. 2016

The Journal of Immunology

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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.

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“…It has been shown that endothelial cells-especially hepatic sinusoidal endothelial cells, a representative RES member-comprise an important part of the innate immune system for eliminating foreign particles from the circulation. Smedsrød and his colleagues (32,36,37) have termed the endocytic endothelial cells as scavenger endothelial cells, leading us to resurrect the concept of the RES (39). A weak point in this effort to re-evaluate the RES is the lack of marker substances that can specify the RES members.…”

mentioning

confidence: 99%

<b>The selective distribution of LYVE-1-expressing endothelial cells and reticular cells in the reticulo-endothelial system </b><b>(RES) </b>

Zheng¹,

Kimura²,

Nio‐Kobayashi³

et al. 2016

Biomed. Res.

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LYVE-1, a receptor molecule for hyaluronan, is expressed in the lymphatic endothelium, blood sinus endothelium, and certain macrophage lineages. The present immunohistochemical study revealed a broader distribution of LYVE-1 in vascular endothelial cells of the murine lung, adrenal gland, and heart as well as the liver and spleen. In addition, sinus reticular cells-including sinuslining cells-in the medulla of the lymph node also intensely expressed LYVE-1. Ultrastructurally, immuno-gold particles for LYVE-1 were localized on the entire length of plasma membrane in all cell types. Most of these LYVE-1-expressing cells had previously been classified as the reticuloendothelial system (RES) specialized for eliminating foreign particles. An LPS stimulation decreased the LYVE-1 expression in macrophages but elevated the expression at mRNA and protein levels in the liver and lung, major organs for the elimination of blood-born waste substances. LYVE-1-expressing endothelial cells in these organs participated in the endocytosis of exogenous particles, and the uptake ability was conspicuously enhanced by the LPS challenge. Although the expression of the degrading enzyme, hyaluronidase, was generally low in the LYVE-1-expressing cells, they were topographically associated with a dense distribution of macrophages possessing hyaluronidase activities in each tissue. These findings suggest that the LYVE-1-expressing cells might be involved in the uptake of hyaluronan and other waste products as well as foreign particles circulating in the blood and lymph while participating in the subsequent degradation in relay with adjacent macrophage populations. LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1) has been identified as a reliable marker that is expressed predominantly in the lymphatic endothelium (5, 29). Both the chemical structure and function of LYVE-1 resemble those of a well-established hyaluronan receptor, CD44, which has a 41% similarity to LYVE-1 and is characterized as an inflammatory leukocyte homing receptor. CD44 is widely expressed in the epithelium, mesothelium, mesenchymal cells, and cells of hematopoietic origin (22), while LYVE-1 has been shown in early studies to display a restricted distribution to the lymphatic endothelium and be completely absent from blood vessels, except for sinusoidal endothelial cells in the spleen (5). Subsequent studies have also detected the expression of LYVE-1 in sinusoidal endothelial cells using paraffin sections of the liver, spleen and lymph node of humans (1, 26). However, our preliminary immunohistochemical study using frozen sections from rodents found a broader distribution of LYVE-1 in the endothelium of other organs, including the lung, adrenal gland, heart, and adenohypophysis. In addition, the sinus reticular cells in the medulla of the lymph node intensely expressed LYVE-1. Interestingly, most of these belong

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The scavenger endothelial cell: a new player in homeostasis and immunity

Cited by 189 publications

References 170 publications

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys

Human Host Defense Cathelicidin Peptide LL-37 Enhances the Lipopolysaccharide Uptake by Liver Sinusoidal Endothelial Cells without Cell Activation

<b>The selective distribution of LYVE-1-expressing endothelial cells and reticular cells in the reticulo-endothelial system </b><b>(RES) </b>

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