Scavenger endothelial cells of vertebrates: A nonperipheral leukocyte system for high-capacity elimination of waste macromolecules

Abstract

I n his pioneering work on the ultrastructure of the hepatic sinusoid 30 years ago, Wisse (1) observed numerous ''smoothwalled macropinocytic vesicles'' in the sinusoidal liver endothelial cells (LEC), suggestive of active pinocytic scavenging of blood plasma proteins. The subsequent finding that the specific activities of lysosomal enzymes in LEC were as high as in the Kupffer cells (2), and for some enzymes even higher, substantiated Wisse's notion. In a series of papers over the next 20 years, it was shown that LEC eliminate an array of soluble macromolecular physiologic and foreign waste products from the circulation by receptor-mediated endocytosis (3-7). It is now well established that the population of LEC in mammals serves as the most important site of elimination of an array of circulating soluble macromolecular waste products. To carry out this scavenger function, LEC express at least five types of specific receptors for endocytosis of major physiologic waste products: (i) the hyaluronan receptor for major matrix polysaccharides and proteoglycans such as hyaluronan and chondroitin sulfate (8); (ii) the collagen alpha-chain receptor for collagen alpha-chains of several types of collagen (9); (iii) the scavenger receptor for amino-terminal propeptides of types I and III procollagen (4), modified macromolecules such as atherogenic advanced glycation end (AGE) products (5) and oxidized LDL (6), oligodeoxynucleotides (10), and blood proteins modified by the process of blood clotting and platelet activation (11); (iv) the mannose receptor for carboxy-terminal propeptide of type I procollagen (7) and tissue plasminogen activator (12); and (v) the Fc-␥ receptor for IgG-antigen immune complexes (13). It is interesting to note that the LEC are able to clear all major categories of biological macromolecules (proteins, polysaccharides, lipids, and nucleic acids) by means of these five types of endocytosis receptors. The blood concentration of most of these substances is normally very low (ng͞ml) because of highly efficient elimination by endocytosis receptors on LEC.On the basis of several studies showing that LEC represent an important nonphagocytic scavenger cell in mammals, it has been suggested that the hepatic scavenger function is shared between Kupffer cells, which eliminate insoluble waste by phagocytosis, and LEC, which remove soluble colloidal or macromolecular waste (3). Hypothesizing that the scavenger function of LEC in mammals be represented by similar nonmacrophagic, nonphagocytic scavenger endothelia in animals of all vertebrate classes, we set out to screen animal species from the seven major vertebrate classes for the presence of scavenger cells equivalent of mammalian LEC.The findings from these studies strongly suggest the presence of a nonmacrophagic system of scavenger endothelial cells that clear the blood from an array of circulating waste macromolecules and colloids. These scavenger endothelial cells make up the backbone of the reticuloendothelial system (RES), and thus represent an import...

Age-related changes in the hepatic microcirculation in mice

“…LSECs play a critical role in the endocytotic removal of blood borne soluble macromolecular waste products (Seternes et al, 2002), like AGEs and other modified proteins and lipoproteins and different products from extracellular matrix turnover. Indeed, the present study showed suppressed endocytotic capacity in the old mice, especially in the centrilobular region, suggesting compromised scavenger function in aging SEC and an agerelated reduction in this important clearance function.…”

Specific endocytosis and degradation of naked DNA in the endocardial cells of cod (Gadus morhuaL.)

“…dead cells, bacteria, large molecular complexes), and they are found in many parts of an animal. In particular, those macrophages residing in close connection to the bloodstream, are highly phagocytic thus functioning as an important element in the reticuloendothelial systemtogether with scavenger endothelial cells in liver of mammals and in the kidney or heart of pisciformes (fish) (Seternes et al, 2002). The endocytic pathway normally confers total degradation of DNA -especially if the DNA is transported to the end-point terminal (lysosomes).…”

“…The endocardial endothelial cells (EEC) lining the muscular trabecula of the Atlantic cod (Gadus morhua L.) heart represent a general vertebrate non-phagocytic scavenger endothelial cell (SEC) system with an extensive capacity to endocytose and degrade soluble physiological and foreign macromolecular waste substances/molecules from the circulation by receptormediated endocytosis (Seternes et al, 2002). Functional studies indicate that the cod aEECs express a set of at least four types of functional endocytic receptors for this purpose: (i) the collagen ␣ chain receptor (Koren et al, 1997;Smedsrød et al, 1995), (ii) the hyaluronan receptor (Seternes et al, 2001b;Sørensen et al, 1997a), (iii) the mannose receptor (Sørensen et al, 2001) and (iv) the scavenger receptor (Seternes et al, 2001a;Sørensen et al, 1998).…”

“…These special endocardial endothelial cells, together with the sinusoidal endothelial cells of the mammalian liver and salmonid kidney have been characterized as scavenger endothelial cells (SEC). Using specific and extremely effective endocytosis they eliminate soluble waste macromolecules from the circulation at a very high rate (Seternes et al, 2002). In vitro studies in cultured atrial endocardial cells have provided functional evidence for the existence of distinct scavenger, mannose and hyaluronan receptors in these endocytically highly active cells (Seternes et al, 2001b;Sørensen et al, 2001;Sørensen et al, 1998).…”

Rat liver sinusoidal endothelial cells (LSECs) express functional low density lipoprotein receptor-related protein-1 (LRP-1)

“…Liver sinusoidal endothelial cells (LSECs) are a specialized type of endothelium, lining the liver sinusoids, that use receptor-mediated endocytosis to take up and degrade numerous physiological and non-physiological soluble macromolecules and colloids from the blood [35]. In addition, through their fenestrations, LSECs act as a dynamic filter facilitating the exchange of substrates between blood and hepatocytes [47].…”