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Review
. 2021 Oct 11:12:757469.
doi: 10.3389/fphys.2021.757469. eCollection 2021.

The Scavenger Function of Liver Sinusoidal Endothelial Cells in Health and Disease

Affiliations
Review

The Scavenger Function of Liver Sinusoidal Endothelial Cells in Health and Disease

Sabin Bhandari et al. Front Physiol. .

Abstract

The aim of this review is to give an outline of the blood clearance function of the liver sinusoidal endothelial cells (LSECs) in health and disease. Lining the hundreds of millions of hepatic sinusoids in the human liver the LSECs are perfectly located to survey the constituents of the blood. These cells are equipped with high-affinity receptors and an intracellular vesicle transport apparatus, enabling a remarkably efficient machinery for removal of large molecules and nanoparticles from the blood, thus contributing importantly to maintain blood and tissue homeostasis. We describe here central aspects of LSEC signature receptors that enable the cells to recognize and internalize blood-borne waste macromolecules at great speed and high capacity. Notably, this blood clearance system is a silent process, in the sense that it usually neither requires or elicits cell activation or immune responses. Most of our knowledge about LSECs arises from studies in animals, of which mouse and rat make up the great majority, and some species differences relevant for extrapolating from animal models to human are discussed. In the last part of the review, we discuss comparative aspects of the LSEC scavenger functions and specialized scavenger endothelial cells (SECs) in other vascular beds and in different vertebrate classes. In conclusion, the activity of LSECs and other SECs prevent exposure of a great number of waste products to the immune system, and molecules with noxious biological activities are effectively "silenced" by the rapid clearance in LSECs. An undesired consequence of this avid scavenging system is unwanted uptake of nanomedicines and biologics in the cells. As the development of this new generation of therapeutics evolves, there will be a sharp increase in the need to understand the clearance function of LSECs in health and disease. There is still a significant knowledge gap in how the LSEC clearance function is affected in liver disease.

Keywords: Fc-gamma receptor IIb; blood clearance; endothelial cell (EC); liver; mannose receptor; scavenger endothelial cells; scavenger receptor; sinusoid.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Fate of extracellular matrix turnover products, the dual cell principle of waste clearance and the role of liver scavenger cells in waste clearance. (A) Molecular fragments are continuously released during the constant turnover of the extracellular matrix. Some of the degradation products are digested locally but a large proportion is drained to lymph nodes where they are endocytosed by macrophages and sinusoidal endothelial cells (Laurent et al., 1986a; Fraser et al., 1997). The fragments that escape uptake in lymph node cells leak to the blood circulation (Østgaard et al., 1995), and are removed from blood by endocytosis in liver scavenger cells. (B) Liver sinusoidal endothelial cells (LSECs) and Kupffer cells, which together make up the largest population of scavenger cells in the body, share the scavenging workload in the liver (Seternes et al., 2002). LSECs are specialized on effective clathrin-mediated endocytosis of soluble macromolecules and nanoparticles, whereas larger particles, such as bacteria and dead and dying cells are cleared by the Kupffer cells, illustrating “the dual cell principle of waste clearance” (Sørensen et al., 2012). (C) The uptake of soluble macromolecules in LSECs are mediated by a range of endocytic receptors, with the mannose receptor, stabilin-1, stabilin-2, and FcγRIIb2 being the most investigated. *Other endocytic receptors may also contribute to the effective waste clearance performed by LSECs. Figure created with BioRender.com.
FIGURE 2
FIGURE 2
Distribution of a soluble scavenger receptor ligand in the hepatic lobule, and ultrastructure of a liver sinusoid. (A) Uptake of FITC-FSA (formaldehyde-treated serum albumin) in mouse liver, 10 min after intravenous administration (dose 2 μg/g bodyweight). Arrows points to FITC-FSA (bright green) located along the sinusoids (S), in a pattern typical of uptake in LSECs. PV, portal vein. (B) Transmission electron micrograph of a rat liver sinusoid. The inserted image is a magnification of part of the LSEC in the main image. Arrows point to coated pits and arrow heads to fenestrae. LSEC, liver sinusoidal endothelial cell; SD, space of Disse; HC, hepatocyte. Scale bar 5 μm.
FIGURE 3
FIGURE 3
Species differences in the localization of main populations of scavenger endothelial cells (SECs). The figure illustrates the organs that harbor the main populations of specialized SECs in different vertebrate classes. #SECs are localized in special gill arteries in hagfish, lamprey (both Agnatha), and ray (Chondrichthyes) (Seternes et al., 2002). § In adult bony fish (Osteichthyes) SECs constitute the endothelium of the venous sinusoids in the kidney hematopoietic tissue in crucian carp (Seternes et al., 2002) and salmonid fish (Dannevig et al., 1990, 1994; Smedsrød et al., 1993; Seternes et al., 2002), and the atrial and ventricular endocardium in Atlantic cod (Smedsrød et al., 1995; Sørensen et al., 1997, 1998, 2001; Seternes et al., 2001a, 2002). In all higher vertebrate classes LSECs represent the major SEC population, studied in frog (Seternes et al., 2002), lizard (Seternes et al., 2002), chicken (Seternes et al., 2002), rodents (Smedsrød et al., 1990b; Seternes et al., 2002; Sørensen et al., 2015), and pig (Nedredal et al., 2003; Elvevold et al., 2004). &In addition to the central scavenger function of LSECs in mammals, studies in rabbit and rodents also show scavenging function of the sinusoidal endothelium in spleen, bone marrow, and lymph nodes (Fraser et al., 1983; Qian et al., 2009; Simon-Santamaria et al., 2014), and in pig, scavenging activity is reported in lung endothelium, in addition to LSECs (Nedredal et al., 2003).

References

    1. Aizarani N., Saviano A., Sagar, Mailly L., Durand S., Herman J. S., et al. (2019). A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 572 199–204. 10.1038/s41586-019-1373-2 - DOI - PMC - PubMed
    1. Akilov O. E., Kasuboski R. E., Carter C. R., McDowell M. A. (2007). The role of mannose receptor during experimental leishmaniasis. J. Leukoc. Biol. 81 1188–1196. 10.1189/jlb.0706439 - DOI - PubMed
    1. Akinc A., Querbes W., De S., Qin J., Frank-Kamenetsky M., Jayaprakash K. N., et al. (2010). Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18 1357–1364. 10.1038/mt.2010.85 - DOI - PMC - PubMed
    1. Alquraini A., El Khoury J. (2020). Scavenger receptors. Curr. Biol. 30 R790–R795. 10.1016/j.cub.2020.05.051 - DOI - PMC - PubMed
    1. Anania J. C., Chenoweth A. M., Wines B. D., Hogarth P. M. (2019). The human fcgammarII (CD32) family of leukocyte FcR in health and disease. Front. Immunol. 10:464. 10.3389/fimmu.2019.00464 - DOI - PMC - PubMed