Am J Physiol Regul Integr Comp Physiol 303: R1217–R1230, 2012.
First published October 17, 2012; doi:10.1152/ajpregu.00686.2011.
Review
Integrative and Translational Physiology: Inflammation
and Immunity in Organ System Physiology
CALL FOR PAPERS
The scavenger endothelial cell: a new player in homeostasis and immunity
Karen Kristine Sørensen,1 Peter McCourt,1 Trond Berg,2 Clive Crossley,3 David Le Couteur,4
Kenjiro Wake,5,6 and Bård Smedsrød1
1
Submitted 21 December 2011; accepted in final form 15 October 2012
Sørensen KK, McCourt P, Berg T, Crossley C, Le Couteur D, Wake K,
Smedsrød B. The scavenger endothelial cell: a new player in homeostasis and
immunity. Am J Physiol Regul Integr Comp Physiol 303: R1217–R1230, 2012.
First published October 17, 2012; doi:10.1152/ajpregu.00686.2011.—To maintain
homeostasis, the animal body is equipped with a powerful system to remove
circulating waste.1 This review presents evidence that the scavenger endothelial cell
(SEC) is responsible for the clearance of blood-borne waste macromolecules in
vertebrates. SECs express pattern-recognition endocytosis receptors (mannose and
scavenger receptors), and in mammals, the endocytic Fc gamma-receptor IIb2. This
cell type has an endocytic machinery capable of super-efficient uptake and degradation of physiological and foreign waste material, including all major classes of
biological macromolecules. In terrestrial vertebrates, most SECs line the wall of the
liver sinusoid. In phylogenetically older vertebrates, SECs reside instead in heart,
kidney, or gills. SECs, thus, by virtue of their efficient nonphagocytic elimination
of physiological and microbial substances, play a critical role in the innate
immunity of vertebrates. In major invertebrate phyla, including insects, the same
function is carried out by nephrocytes. The concept of a dual-cell principle of waste
clearance is introduced to emphasize that professional phagocytes (macrophages in
vertebrates; hemocytes in invertebrates) eliminate larger particles (⬎0.5 ␮m) by
phagocytosis, whereas soluble macromolecules and smaller particles are eliminated
efficiently and preferentially by clathrin-mediated endocytosis in nonphagocytic
SECs in vertebrates or nephrocytes in invertebrates. Including these cells as
important players in immunology and physiology provides an additional basis for
understanding host defense and tissue homeostasis.
liver sinusoidal endothelial cell; endocytosis; blood clearance; scavenger cells;
nephrocyte
Major Cellular Waste Clearance Systems
EVERY SECOND, THE ANIMAL BODY is challenged with waste
material, both self-made and foreign. Most macromolecules in
the body are highly dynamic structures, with natural turnover
rates spanning from minutes to months. This natural turnover
includes some limited extracellular degradation, but in fact,
complete degradation to single building blocks (amino acids,
1
The term “waste” is defined here as material whose presence in the blood
is incompatible with homeostasis.
Address for reprint requests and other correspondence: B. Smedsrød, Vascular Biology Research Group, Dept. of Medical Biology, Univ. of Tromsø,
NO-9037 Tromsø, Norway (e-mail: [email protected]).
http://www.ajpregu.org
monosaccharides, fatty acids, and nucleotides) will primarily
take place after uptake and intralysosomal processing in specialized scavenger cells. In addition to natural turnover mechanisms, chemical and mechanical wear-and-tear processes constantly turn macromolecules into harmful waste substances,
such as advanced glycation end products and oxidized lipoproteins that are recognized and eliminated by the same scavenger
cells. Moreover, foreign material (primarily microbes and microbial products) that constantly invade the body are removed
by these scavenger cells.
Cells responsible for the removal of waste macromolecules
have long been the subject of research in immunology, metabolism, and physiology. About 150 years ago, the tradition of
injecting “vital stains”, i.e., colloidal dyes, into living organ-
0363-6119/12 Copyright © 2012 the American Physiological Society
R1217
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Vascular Biology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø,
Tromsø, Norway; 2Department of Biology, University of Oslo, Blindern, Oslo, Norway; 3Institute for Marine and Antarctic
Studies, University of Tasmania, Hobart, Tasmania, Australia; 4Centre for Education and Research on Ageing and the
ANZAC Research Institute, Concord Repatriation General Hospital and the University of Sydney, Sydney, New South Wales,
Australia; 5Tokyo Medical and Dental University and Liver Research Unit, Tokyo, Japan; and 6Minophagen Pharmaceutical
Company Limited, Tokyo, Japan
Review
R1218
SCAVENGER ENDOTHELIAL CELLS
SECs
In mammals, birds, reptiles, and amphibians, the body’s
largest SEC reservoir is located in the liver, where they make
up the entire hepatic sinusoidal endothelium (136). Interestingly, phylogenetically older vertebrates carry their SECs in
organs other than the liver. Thus, bony fish have their SECs in
either heart (endocardium) or kidney (venous sinusoids),
whereas in the cartilagenous fish and the jawless vertebrates
hagfish and lamprey, SECs are located in special blood vessels
of the gills (136). The vast majority of the literature on SEC
scavenger function and receptor expression deals with the
mammalian liver sinusoidal endothelial cell (LSEC). Accordingly, the following outline of the special features of SECs
refers mainly to the mammalian LSEC.
LSEC
The numerous sinusoids of liver are lined by an endocytically highly active endothelium, which efficiently eliminates
large amounts of circulating macromolecules of foreign and
endogenous origin (142). The LSECs were first distinguished
from the resident liver macrophages or Kupffer cells in rat, on
the basis of ultrastructure, by Wisse in 1970 (171). These
endothelial cells lack a basal lamina and are characterized by
numerous fenestrae (diameter ⬃150 nm) without diaphragms,
allowing passage of molecules between the sinusoidal lumen
and the underlying hepatocytes (Fig. 1) (10). The fenestrations
act as a permeable and selective ultrafiltration system, which is
important for the hepatic uptake of many substrates, and
fenestrae size affects the balance of different lipoprotein moieties in plasma, modulating cholesterol metabolism and, thus,
susceptibility to atherosclerosis (34, 172).
In his pioneering work, Wisse (171) also noted numerous
endocytic vesicles that suggested active endocytosis of blood
plasma proteins. A physiological role of the scavenger activity
of these cells was revealed for the first time when their very
active endocytosis of the connective tissue macromolecule
hyaluronan was discovered in 1982 (144). Later studies revealed that LSECs are the major elimination site for an array of
physiological and pathophysiological waste macromolecules
and carry high-affinity endocytosis receptors that efficiently
mediate the uptake of a great number of waste substances
(Table 1 and Fig. 2). In addition, these cells avidly pinocytose
small and colloidal particles, such as colloidal silver and latex
beads ⬍200 nm (122), but they are not normally phagocytic (67).
Endocytosis Receptors on LSEC
Scavenger receptors. The term “scavenger receptor” (SR)
was originally coined to describe a macrophage receptor that
mediates endocytosis of a broad range of polyanionic molecules (39). However, this term has now become the common
name for an expanding number of identified SRs with various
ligand specificities/affinities expressed on a number of different tissues and cells, including the LSEC. Currently, there are
eight known structurally unrelated SR subclasses (SR-A to
SR-H) that recognize common ligands (104).
The LSEC expresses SR-A (also known as macrophage SR)
(52), SR-B (SR-B1 and CD36) (86), and SR-H (stabilin-1/
FEEL-1 and stabilin-2/FEEL-2/HARE) (1, 42, 94, 120, 177).
SR-D (CD68), SR-E (LOX-1), SR-F (SREC), and SR-G (SRPSOX) are not normally expressed on LSECs (24). The main
work-horse SR on this cell type appears to be SR-H/stabilin-2
(possibly together with stabilin-1; Table 1) based on the following: 1) SR-A knockout mice clear SR ligands equally well
as wild-type mice (79, 159, 165), and cultured LSECs from the
same knockout mice endocytose and degrade SR ligands
equally well as wild types (41); 2) an antibody to CD36 that
inhibits CD36-mediated uptake of SR ligands in other cells has
no effect on the uptake of SR ligands by LSECs (107); and
3) an antibody to stabilin-2 can inhibit the LSEC-mediated
uptake of hyaluronan by more than 80% and other SR ligands
by more than 50% (94).
Stabilin-1 and stabilin-2 are 41% homologous and mediate
the uptake and degradation in LSECs of oxidized low-density
lipoproteins (LDL) (76), extracellular matrix macromolecules,
and protein turnover by-products (94) that could otherwise
accumulate in vascular tissues and interfere with homeostasis.
Advanced glycation end-products (AGEs) and SPARC (secreted protein acidic and rich in cysteine, also known as
osteonectin and BM-40) have also been identified as ligands
for the LSEC stabilins (42, 66).
Although the two stabilins have a largely similar ligand
profile (Table 1), there are some important differences: stabilin-1 binds SPARC but not hyaluronan, and stabilin-2 binds
hyaluronan but not SPARC. Another difference is their organ
and intracellular distribution. High expression of stabilin-2
appears to be restricted to fenestrated endothelium, e.g., in liver
sinusoids (31), bone-marrow sinusoids (126), lymph nodes
(89), and choriocapillaris (75). These endothelia also show
high endocytic activity. Comparative studies in lower vertebrates show stabilin-2 expression in cod endocardial endothelial cells (Fig. 3), which represents the major SEC population
of this species (154, 155). Stabilin-1, while being expressed on
the same endothelia as stabilin-2 in mammals, is also found on
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isms to identify anatomical sites of waste accumulation began.
After several decades of such studies, Aschoff (3) in 1924
summed up the state-of-the-art and launched the concept of
“the reticuloendothelial system” (RES), which included both
macrophages and cells lining the sinusoids of liver, lymph
nodes, spleen, bone marrow, and adrenal and pituitary glands.
The role of the macrophage in uptake and degradation of waste
substances was extensively studied over the years that followed
after Aschoff’s publication, leading to a major focus on the role
of macrophages in this process. The past three or four decades
has led to a significant development in our understanding of the
waste generating and disposal processes in the body, and we
now know 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) in vertebrates (136). Clearly, a
deeper knowledge of the SEC, which is much less studied than
the macrophage, will provide insight into disease formation,
and blood clearance functions, i.e., the beneficial elimination of
blood-borne virus and other pathogens, as well as unwanted
uptake of biopharmaceuticals. This review focuses on the least
studied of these two cell types, namely the SEC, and the role
of these cells in tissue homeostasis and host defense. In the last
part of the review, we argue that the nephrocyte, an essential
pinocytic cell of many invertebrate phyla, carries out a scavenger function with striking analogy to the vertebrate SEC.
Review
R1219
SCAVENGER ENDOTHELIAL CELLS
A
B
HC
HC
SD
LSEC
SD
LSEC
1 µm
C
1 µm
D
D
5 µm
1 µm
Fig. 1. Morphology of scavenger endothelial cells in mammalian liver. A: scanning electron micrograph (EM) of a mouse liver sinusoid. The liver sinusoidal
endothelial cells (LSECs), which are specialized scavenger endothelial cells, are highly fenestrated. Arrows point to LSEC fenestrae arranged in sieve plates.
SD, space of Disse (the subendothelial space); HC, hepatocyte. B: transmission EM of rat liver sinusoid. Arrows point to clathrin-coated pits, and arrowheads
point to fenestrae in LSECs. SD, space of Disse; HC, hepatocyte. C: scanning EM of rat LSEC culture on day 0. The cells are all highly fenestrated. D: high
magnification of inset in C showing details of cell fenestration (arrows).
alternatively activated macrophages (120). Recent data suggest
that stabilin-1 is expressed in foam cells (11), and stabilin-2 is
expressed in endothelial cells abutting atherosclerotic plaques
(72). Interestingly, during embryonic development, stabilin-2
is expressed in all liver vascular endothelia, while becoming
restricted to the liver sinusoids at embryonic day 19.5 in mouse
(175). In mature LSECs, stabilin-2 can be found throughout the
cell and on the cell surface. Stabilin-2 is associated with
various structures associated with endocytosis, while stabilin-1
appears to have a predominantly intracellular distribution.
However, stabilin-1 in LSECs, like stabilin-2, is associated
with clathrin and adaptor protein-2 (42), mediates uptake of
oxidized LDL and formaldehyde-treated serum albumin (76),
and rapidly cycles between the cell surface and endosomes
(125). A recent study reporting that stabilin-1/2 double-knockout mice had mild liver fibrosis and also severe kidney pathology suggests that the stabilins are vital for the removal of
compounds toxic for the kidneys (130).
In summary, stabilin-1 and -2 appear to be the main SRs for
circulating colloidal and soluble macromolecular waste in the
mammalian LSEC (Table 1), but their scavenging function can
be replaced somewhat in stabilin-1/2 double knockout mice.
Mannose receptor. Another important LSEC endocytosis
receptor is the mannose receptor (CD206), a 175–180-kDa
type I integral membrane protein belonging to the C-type lectin
family (96). The receptor mediates uptake of a wide range of
endogenous glycoproteins and microbial glycans and has a
proposed role both in immunity (157) and glycoprotein homeostasis (73, 150).
The mannose receptor is expressed in several mammalian
cell types, including LSECs (27, 83, 87, 89), sinusoidal endothelial cells of lymph nodes (89), subpopulations of immature
dendritic cells (DCs) (96), and tissue macrophages (157).
However, its expression in Kupffer cells is debatable. It is
absent in human Kupffer cells (89), and its expression in rat
and mouse Kupffer cells is low compared with LSECs (78, 83).
This is supported by the consistent observation that soluble
mannose receptor ligands are taken up in the LSECs, rather
than in Kupffer cells and other macrophages, following their
intravenous injection (142).
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HC
Review
R1220
SCAVENGER ENDOTHELIAL CELLS
Table 1. Ligands cleared from the blood circulation mainly by the mammalian liver sinusoidal endothelial cells and their
corresponding endocytosis receptors
Ligand
Receptor
Stabilin-2a
Stabilin-2a
SR
Stabilin-2b
SR
SR, stabilin-2
Mannose receptorc
Mannose receptor
Mannose receptor
Mannose receptor
Mannose receptor
(94, 149)
(45, 149)
(148)
(45, 115)
(117)
(94, 98)
(87, 145, 150)
(147)
(143)
(25, 51, 53)
(111)
SR, stabilin-1, stabilin-2
SR, stabilin-2 (stabilin-1d)
(76, 164)
(43, 146)
Fc-␥RIIb2
(102)
SR
Mannose receptor
Mannose receptor
Mannose receptor
Mannose receptor
Mannose receptor
Unknown
(90)
(28)
(4)
(84)
(83)
(123)
(151)
SR, stabilin-1, stabilin-2
SR (stabilin-1/stabilin-2d)
Mannose receptor
Mannose receptor
Unknown
(6, 76)
(106)
(123)
(123)
(60)
SR: Scavenger receptor; type of SR not yet established. AGE, advanced glycation end-product; LDL, low-density lipoprotein. Stabilin-1 synonym: FEEL-1
[fasciclin endothelial growth factor (EGF)-like, laminin-type EGF-like and link domain-containing scavenger receptor 1] (1). Stabilin-2 synonyms: FEEL-2,
HA/SR (hyaluronan/SR), HARE (hyaluronan receptor for endocytosis) (94, 160, 177). aUntil 1999, the uptake of hyaluronan and chondroitin sulfate in the liver
sinusoidal endothelial cells (LSEC) was thought to occur via a special hyaluronan receptor, distinct from the SRs on these cells. The purification and
characterization of the hyaluronan receptor in 1999 revealed that it also binds typical SR-ligands (94), and in 2002, this receptor was officially named stabilin-2
(120). bØie et al. (115) reported that heparin is taken up in LSECs via another, not yet identified, receptor. cUntil 2007, it was believed that the LSEC expressed
a specific collagen ␣-chain receptor, distinct from the mannose receptor. In 2007, Malovic et al. (87) found that the collagen ␣-chain binding receptor on LSEC
is the mannose receptor. However, collagen ␣-chains and mannose-terminated ligands have affinity to nonoverlapping binding sites on the receptor.
d
AGE-albumin affinity to stabilin-1, as well as acetylated LDL affinity to stabilin-1 and stabilin-2 have been studied in transfected cell lines only (1, 160).
Mannose receptor-deficient mice show elevated levels of
lysosomal enzymes in plasma, and increased fetuin B and
C-terminal procollagen propeptides in sera, compared with
control mice (73). These molecules are upregulated during
A
inflammation and wound healing and are cleared from the
bloodstream mainly in LSECs (25, 147). In fact, LSECs were
shown to depend on the mannose receptor for recruitment of
lysosomal enzymes to maintain normal degradation capacity
B
s
CV
s
50 µm
20 µm
Fig. 2. Endocytosis in liver sinusoidal endothelial cells (LSECs). A: fluorescence micrographs of a rat liver section following double intravenous injection of 0.5 mg
TRITC-labeled formaldehyde-treated albumin (red), a substance endocytosed by LSECs (6) and 5 ⫻ 108 FITC-labeled latex beads (2 ␮m diameter; green), which are
taken up in Kupffer cells (KCs). CV, central vein; s, sinusoid. [Reproduced from Elvevold et al. (26)]. B: endocytosis of denatured collagen in mouse LSECs. Primary LSEC
cultures (day 0) were incubated at 37°C for 2 h with 10 ␮g/ml DTAF-labeled denatured collagen, a ligand for the LSEC mannose receptor (87). Ligand uptake is seen in green
discrete vesicles throughout the cell cytoplasm. TRITC, tetramethyl rhodamine isothiocyanate; FITC, fluorescein isothiocyanate; DTAF, 5-isomer of fluorescein dichlorotriazine.
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Tissue turnover waste products
Hyaluronan
Chondroitin sulfate
Nidogen
Heparin
Serglycin
N-terminal propeptides of procollagen (I, III)
Collagen alpha chains (I, II, III, IV, V, XI)
C-terminal propeptide of procollagen type I
Tissue plasminogen activator
Lysosomal enzymes
Salivary amylase
Modified proteins and lipoproteins
Oxidized LDL
AGE-albumin
Immune complexes
Soluble IgG immune complexes
Ligands of nonmammalian origin
CpG oligodeoxynucleotides
Invertase
Mannan
Ovalbumin
Ricin
Horseradish peroxidase
Aminated ␤(1-3) glucan
Nonphysiological model ligands
Formaldehyde-treated albumin
Acetylated LDL
Agalacto-orosomucoid
Ahexosamino-orosomucoid
Lithium carmine
Reference
Review
R1221
SCAVENGER ENDOTHELIAL CELLS
A
B
hl
e
m
50 µm
D
10 µm
Fig. 3. Scavenger function and tissue location of SECs in a lower vertebrate. LSECs in fish and other lower vertebrates do not have a scavenger function, but
depend instead on SECs in kidney, heart, or even gills for removal of blood-borne colloids and waste macromolecules (136). Cod SECs are shown as an example.
A: scanning EM of the endocardium of cod heart atrium. The muscular trabeculae are lined with high endothelial cells (arrows), which are interconnected at the
base of the cells. Cod SECs exhibit high endothelial morphology, similar to SECs in gills of hagfish. B: fluorescence micrograph of a section of cod atrium 1
h after intravenous injection of FITC-hyaluronan, a ligand for stabilin-2 in mammals (94, 120). The fluorescence can be seen in discrete vesicles throughout the
cytoplasm of the endocardial endothelial cells (arrows). e, endothelium; m, myocardium; hl, heart lumen. [Reproduced from Sørensen et al. (153) with kind
permission from Springer Science⫹Business Media: Cell Tissue Res, Role of endocardial endothelial cells in the turnover of hyaluronan in Atlantic cod (Gadus
morhua), vol. 290, 1997, p. 101–109, Sørensen KK, Dahl LB, Smedsrød B]. C: uptake of FITC-LPS in cod endocardial SEC culture. The cells were incubated
with FITC-LPS for 1 h at 12°C. The fluorescence is confined to endocytic vesicles (arrows). [Reproduced from Seternes T, Dalmo RA, Hoffman J, Bogwald
J, Zykova S, Smedsrød B. Scavenger-receptor-mediated endocytosis of lipopolysaccharide in Atlantic cod (Gadus morhua L.). J Exp Biol 204: 4055– 4064,
2001.] FITC, fluorescein isothiocyanate; LPS, lipopolysaccharide from Vibrio salmonicida. D: stabilin-2 expression in cod endocardial SEC. Western blot
showing that purified lysates from cod atrial endocardial endothelial cells (24,000 cells), pig liver sinusoidal endothelial cells (LSECs) (20,000 cells), and rat
LSECs (5,000 cells) all contain stabilin-2 epitopes that react with an antibody to whole rat stabilin-2 (94, 120).
for endocytosed material (25). Other physiological ligands for
this receptor in LSECs include tissue-type plasminogen activator (143), neutrophil granulocyte-derived myeloperoxidase
(137), salivary amylase (111), and denatured collagen fragments (87) (Table 1). These molecules are released to the body
fluids during normal and pathophysiological tissue turnover
and may be harmful to the organism if allowed to accumulate.
The extraordinarily broad ligand specificity of the mannose
receptor is explained by its three different ligand binding
regions: 1) an outer cysteine-rich amino-terminal domain,
which recognizes specific sulfated sugars (32); 2) a fibronectin
type II repeat, which binds collagens (108), and 3) a series of
eight adjoining carbohydrate recognition domains (also named
C-type lectin-like domains) that bind glycoproteins and glycolipids exposing D-mannose, L-fucose, and/or N-acetyl-D-glucosamine in terminal position of their sugar side chains (29, 161).
There is little or no competitive inhibition of ligands for the
different domains, which explains why it was believed for
more than 20 years that LSECs carried a distinct collagen
␣-chain receptor (142, 145). The LSEC collagen ␣-chain
receptor was found to be identical to the mannose receptor
(87). This receptor clearly plays a vital role in homeostasis in
that the normal remodeling of bone by osteoclasts releases
more than half a gram of partially degraded collagen into the
bloodstream per day in humans, and this material is efficiently
cleared by LSEC (87).
The mannose receptor expression in liver is influenced by
inflammatory stimuli and cytokines. IL-1 upregulates receptor
expression, and endocytosis via this receptor in LSECs (2), whereas
IL-10 diminishes the LSEC mannose receptor activity (64).
Fc gamma-receptor IIb2. Although hepatic Fc-gamma-receptor- (Fc␥R)-mediated clearance of circulating IgG immune
complexes was previously assumed to be mediated by Kupffer
cells only (33), we now know that the LSEC also contributes
importantly to the uptake of small soluble immune complexes
(46, 57, 81, 140). Using immune complexes consisting of
dinitrophenylated (DNP) albumin in complex with anti-DNP
IgG, Skogh et al. (140) found following intravenous injection
in rats that the proportions removed by Kupffer cells and
LSECs depended on the number of antibodies in complex with
DNP-albumin. The larger the complex the more was directed
to Kupffer cells (140). A similar size dependency is also
observed when comparing uptake of SR-ligands in Kupffer
cells, and LSECs (56, 76, 146).
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C
10 µm
Review
R1222
SCAVENGER ENDOTHELIAL CELLS
Endocytosis Mechanisms and Metabolism
Endocytosis mechanisms. The main type of receptor-mediated endocytosis in LSECs is clathrin-dependent. The cells are
well equipped with molecules involved in clathrin-dependent
endocytosis and contain approximately twice as many clathrincoated pits per membrane unit than hepatocytes and Kupffer
cells (62). LSECs also express caveolin (86), and at least one
receptor that mediates endocytosis (Fc␥RIIb2) has been observed in lipid rafts (102), but uptake (“podocytosis”) via
caveolae has not been demonstrated, and fluid phase endocytosis is negligible as an entrance gate for waste macromolecules (62).
The internalization rate for mannosylated albumin bound to
the mannose receptor is only 10 –15 s (84), which is 10-fold
faster than internalization via the asialoglycoprotein-receptor
in hepatocytes (84). Both stabilins (42), Fc␥RIIb2 (102) and
the mannose receptor (85) are recycled from the early endosomes to the cell surface, so these receptors, therefore, mediate
uptake of ligands at a relatively constant rate over time. Even
the ligands may to some extent be recycled. This has been
demonstrated particularly well for endocytosis via the
Fc␥RIIb2 (102) but may also occur for mannose receptor
ligands (85) due to incomplete dissociation of ligand from the
receptor in the early endosome.
Following intravenous injection (into rodents) of ligands that
typically distribute to LSEC, such as collagen ␣-chains, formaldehyde-treated albumin, and AGE-albumin, degradation products
usually appear in the circulation already within 10 –12 min (25,
87, 146). The transport of ligand along the LSEC endolysosomal
route proceeds sequentially via early endosome antigen 1-positive
endosomes (48), lgp120 (rat lysosomal membrane glycoprotein
120)-positive late endosomes (61), and, finally, via lysosomes
where degradation is completed (48, 61). Degradation of collagen
␣-chains begins already in the early endosomes (48).
The pathways followed by immune complexes internalized
by the Fc␥RIIb2 in LSECs deviate from those followed by
ligands of the mannose receptor and SRs. The internalized
immune complexes are largely returned to the cell surface (80,
102), leading to a slow net internalization of cell-surface bound
ligand (half time of internalization ⬃15 min compared with ⬍1
min by mannose receptors and SRs). A consequence of the
extensive recycling of immune complexes is that a relatively
small proportion (about 10%) of internalized ligand is directed
to later parts of the endocytic pathway. Whereas activated
Fc␥Rs are downregulated following ligand binding in other
immune cells (8, 163), the Fc␥RIIb2 is not degraded as a result
of endocytosis of immune complexes in LSECs (102). The
functional significance of the extensive recycling of immune
complexes bound to its receptor in LSECs is not known.
LSEC metabolism. The high-capacity uptake and degradation activities of the LSECs place these cells as an important
metabolic actor in liver. The cells are equipped with very high
levels of lysosomal enzymes (25, 65) to maintain the high
catabolic activity needed to degrade all of the waste macromolecules that constantly enter the blood. Using biosynthetically 14Cor 3H-labeled hyaluronan, or a chondroitin sulfate proteoglycan
labeled biosynthetically in the sugar moiety with 14C, 3H, or
[35S]sulfate, or chemically with [125I] in the tyrosine groups of the
core protein, it was found that the endocytosed macromolecules
were degraded intralysosomally in LSECs by acid hydrolases
to basic building blocks (amino acids, monosaccharides, and
sulfate) that were then transported across the lysosomal membrane for further processing of the monosaccharides to lactate
and acetate, that were, in turn, transported out of the cells (30,
141). It is worth noting that lactate is a major product released
by LSECs independently of degradation of endocytosed macromolecules in rat (91) and pig (109, 110). The high production
of lactate by LSECs signifies that their metabolism is largely
anaerobic, which is supported by the facts that the cells 1) carry
few mitochondria (7), and 2) operate in the O2-poor environment of the hepatic sinusoid (91).
LSEC Immune Functions
Role in innate immunity. LSECs contain pattern recognition
receptors, the two most important being the mannose receptor
and SRs. These receptors recognize a number of structures
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Mousavi et al. (102) demonstrated that Fc␥RIIb2 is the only
Fc␥R in rat LSECs. The expression of Fc␥RIIb2 in rat and
human LSEC is unique and can be used as a biomarker for
these cells (88). In mouse, 72% of the total body pool of
Fc␥RIIb2 is expressed in the liver, and 90% of this is associated with LSECs (36).
Other endocytic receptors. The SRs, mannose receptor, and
Fc␥RIIb2 constitute the main waste-clearing receptors on
LSEC (Table 1). In addition, several other receptors are expressed in these cells that may be involved in scavenging
activity. Recently, Øie et al. (114) reported the presence of a
functional LRP-1 (low-density lipoprotein receptor-related
protein-1) in LSECs, mediating endocytosis of trypsin-activated alpha 2-macroglobulin and receptor-associated protein in
these cells. In liver, this receptor is mainly expressed in
hepatocytes, and only around 10% of the liver LRP-1 activity
is expressed in the LSECs. This finding suggests another role
for LSECs in liver lipid homeostasis, besides the structural
lipid filtration function of their cell fenestrae.
Other receptors include L-SIGN (liver/lymph node-specific
ICAM-3 grabbing non-integrin; DC-SIGNR), LSECtin (liver
and lymph node sinusoidal endothelial cell C-type lectin;
DC-SIGN), and LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1) (69, 119, 124). L-SIGN binds virus, including hepatitis C virus (38) and human immunodeficiency virus
(119), whereas LSECtin, which is predominantly expressed on
LSECs, is potentially involved in the regulation of immune
responses in liver through interaction with L-SIGN in response
to hepatitis C virus (77). However, the role of these receptors
in LSEC endocytosis is unknown.
LYVE-1 is a hyaluronan-binding protein and is expressed
in lymphatic vascular endothelium and sinusoidal endothelia of lymph nodes, liver, and spleen (5, 103, 124), as well
as in subsets of tissue macrophages coexpressing stabilin-1
(129). Initially, the role assigned for this receptor was
hyaluronan clearance from lymph (124), but the receptor is
also suggested to be involved in lymphangiogenesis, wound
healing, and tumor formation (129). Its expression in normal
liver is restricted to LSECs (103, 113). Of note, stabilin-2
(previously known as the hyaluronan receptor) is the major
endocytic receptor for hyaluronan in LSEC (94, 149), and
the relative contribution (if any) of LYVE-1 in this process
is unknown.
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SCAVENGER ENDOTHELIAL CELLS
antigen processing and presentation with similar efficacy as
those of DCs. However, in contrast to conventional antigenpresenting cells, LSECs fail to induce differentiation of naive
CD4⫹ T cells toward a Th1 phenotype. This feature of LSECs,
along with the production of negative immune modulatory
cytokines by LSEC-primed T cells upon restimulation, is
suggested to contribute to the unique hepatic immune tolerance
(16). In this model, the LSEC represents the sessile, organresident antigen-presenting cell-inducing local tolerance in the
liver toward soluble antigens, such as food antigens or selfproteins. This view of LSECs as functional antigen-presenting
cells was challenged by Katz et al. (58). They reported that,
unlike DCs, LSECs have low or absent expression of MHC II,
and CD86, and are poor stimulators of allogeneic T cells,
despite high capacity for antigen uptake in vitro and in vivo.
They concluded that LSECs alone are insufficient to activate
naive T cells. Of note, a study by Onoe et al. (116), in contrast
to the results of Katz et al. (58) but in agreement with Knolle
and Gerken (63), concluded that primary LSECs from mice do,
indeed, express MHC II and CD86. The conflicts associated
with the expression of MHC II in LSECs are further underlined
by earlier studies that failed to demonstrate this molecule on rat
or human LSECs (80, 131). Obviously, further studies are
needed to elucidate the role of LSECs in adaptive immunity.
Role of the LSEC in Age-Related Conditions
Distinct age-related changes in otherwise healthy livers are
described in mouse, rat, baboon (Papio hamadryas), and human (15, 54, 70, 71, 97, 169) and in two premature aging
syndromes transgenically induced in mice (40, 92). These
changes include increased endothelial thickness, and loss of
cell porosity, changes in endothelial cell markers, and sporadic
depositions of basal lamina and collagens in the subendothelial
space (the space of Disse). This may have important implications for lipid transfer between blood and hepatocytes, which
normally occurs through the liver sieve (71). The reduced
LSEC porosity leads to impaired blood clearance of lipids after
meals, because circulating triglyceride-rich chylomicron remnants produced from dietary fat are hindered from entering the
space of Disse (34, 49). Defenestration may, therefore, exacerbate postprandial hypertriglyceridemia, which is a common
condition in old age and a major risk factor for atherosclerosis
(71). Interestingly, age-related defenestration can be prevented
by caloric restriction (55) and the sirtuin-activator, resveratrol
(68), and reversed by the serotonergic drug, 2,5-dimethoxy-4iodoamphetamine (35).
Although a signature function of LSECs is their enormous
endocytic capacity, only a few reports have addressed this
issue in relation to aging. These studies have all used modified
(heat-aggregated or chemically treated) albumin as model substances. Typically, such modifications lead to neutralization of
positively charged amino groups, increasing the net negative
charge of the protein and thus their affinity for SRs (22, 166).
Results are not fully consistent (12), but most point to significantly reduced LSEC endocytic capacity at old age (14, 47,
54, 138).
In addition to the negative effect of hepatic defenestration on
blood lipid contents, a decreased LSEC endocytic capacity in
old individuals will further increase the risk for deposition of
potentially dangerous waste macromolecules in extrahepatic
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carried by microbes and their products, or so-called pathogenassociated molecular patterns (PAMPs), as well as potentially
harmful endogenous ligands, such as matrix fragments, DNA,
and other molecules leaking from injured or dying cells (100).
Interestingly, the PAMPs recognized and scavenged by the
LSEC fit the definition of DAMPs, or danger-associated molecular patterns (93).
LSECs also express Toll-like receptors (TLRs), which are
major regulators of innate immune responses against viruses,
bacteria, fungi, and protozoa (59). So far, TLR9 and TLR4
have been identified in LSECs (90, 162), and indirect evidence
points to LSEC expression of TLR2 (50). A recent study
reported that murine LSECs produced TNF-␣ when treated
with ligands for TLR1, TLR4, TLR6, TLR8, and TLR9, and
IL-6 by agonists for TLR3 and TLR4, and interferon-␤ following treatment with TLR3 ligands (174). Thus, future studies
are likely to reveal the existence of several types of TLRs in
these cells. TLR9 recognizes microbial DNA, in particular,
immune stimulating unmethylated CpG motifs. Because TLR9
is localized in the endolysosomal compartment, CpG must first
bind to an endocytosis receptor (probably stabilin-1 and/or
stabilin-2) expressed on the surface of LSEC, which transports
it to the compartment where TLR9 is located (90). Upon
binding to its ligand, TLR9 in LSECs initiates cytosolic
MyD88-mediated signaling leading to translocation of NF-␬B,
and eventually to production and release of IL-1 and IL-6.
TLR4 binds LPS in various cell types, including the LSEC
(162). Although TLR4 is expressed on the cell surface, additional molecules are required for successful binding to LPS;
LPS binds to LPS-binding protein (LBP) in blood, and this
LPS-LBP complex is subsequently recognized by CD14, a
molecule expressed not only in phagocytes, but also in LSECs
(131). LPS recognition is followed by increased physical
proximity between CD14 and TLR4, suggesting that CD14 and
TLR4 may interact in LPS signaling. MD-2 is another protein
that has an important role in the LPS response by macrophages,
DCs, and B cells, and probably also in LSECs (173).
The presence of Fc␥RIIb2, a type of receptor normally
associated with cells of the immune system places LSEC in a
unique position among the endothelial cells of the body. In
fact, LSECs and placental endothelial cells are the only endothelia that have so far been reported to express this receptor
(82, 102).
Role in uptake of blood-borne virus. Most virus and phage
particles represent small particles, or colloids, less than 200 nm
in diameter, that are taken up by pinocytosis rather than
phagocytosis (128). Therefore, it is likely that several bloodborne viruses are cleared by the highly endocytically active
LSEC. The uptake of virus has traditionally been studied in
connection with disease-forming virus, and the important research field exploring how a virus infects cells has not factored
in the naturally high scavenger capacity of the LSECs. A recent
study showed that 90% of adenovirus 1 injected into mice
ended up in the LSEC (37). Therefore, one may speculate that
most viruses that reach the blood are eliminated “silently” by
uptake and degradation in the LSEC, without causing any
infection.
Role in adaptive immunity. The LSECs has been implicated
as an inducer of immune tolerance in the liver. Knolle and
Gerken (63) reported that LSECs express MHC II and the
costimulatory molecules CD40, CD80, and CD86 and perform
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SCAVENGER ENDOTHELIAL CELLS
tissues, which may lead to systemic complications. The risk
may be especially important in situations with a sudden increase in circulatory waste loads, such as in massive trauma or
disseminated intravascular coagulation, as well as in long-term
conditions, such as obesity and diabetes, in which there is an
increased burden of modified proteins and lipoproteins that are
normally efficiently removed by LSEC.
f
A
Invertebrate Analogs to the Vertebrate SEC
True endothelial cells are only found in vertebrates (13), but
insect hemocytes and nephrocytes have similar scavenger functions to vertebrate macrophages and SECs, sharing the task of
waste clearance and defense against foreign intruders (20,
136). Hemocytes represent the primary phagocyte and are
B
tr
ht
n
n
ht
N
N
N
m
m
f
al
g
C
100 µm
D
n
bm
*
cp
*
*
*
ht
n
bm
1 µm
E
n
cr
*
n
5 µm
*
0.5 µm
Fig. 4. Endocytosis in insect nephrocytes (3rd instar Calliphora larva). A: Calliphora larva dissected 24 h after hemocoel injection with 0.4% trypan blue in
physiological saline for insects (17, 19). Only the pericardial nephrocytes (n) and perioesophageal nephrocytes (garland cells; g) sequester this blue vital dye.
The unstained heart (ht) with blue-stained lateral nephrocytes (n) run horizontally parallel to a tracheal trunk (tr), and the garland cells (g) surround the esophagus
(lower right). Malphigian tubules (m, chalky white or yellow) and fat body cells (f) remain unstained. B: scanning EM of heart and nephrocytes in the posterior
abdominal region of the larva. The heart (ht) and giant pericardial nephrocytes (N) are suspended from the abdominal wall by elastic connective tissue strands
and are stretched by alary muscles (al). Smaller nephrocytes (n) occupy the pericardial space and extend anteriorly along the heart. All nephrocytes are bathed
in hemolymph and are strategically situated in areas of maximal blood flow. C: low-magnification transmission EM showing nephrocyte (n) lying alongside the
contracted heart muscle (ht). A thin basal membrane (bm) encloses the nephrocytes, while a much thicker basal membrane encloses the muscular tissue of the
heart. The cortical region (cr) of the nephrocytes contains numerous labyrinthine channels (highlighted by * in D). D: transmission EM of the cortical region
of a nephrocyte. Note the podocyte configuration, with deeply infolded plasma membranes, forming channels studded with numerous coated pits (arrows) and
coated vesicles. These labyrinthine channels (*) are separated from hemolymph by a thin basal membrane (bm) and filter slits (arrowheads), which together serve
as a hemolymph ultrafilter. E: immune transmission EM of the cortical region of a nephrocyte, showing FITC-labeled formaldehyde-treated albumin uptake in
endosomes 1 h after injection into the hemocoel. The localization of FITC-formaldehyde-treated albumin is visualized by 10-nm gold particles (black dots;
arrows). The endocytosed ligand was detected with a mouse anti-FITC-antibody, rabbit anti-mouse antibody, and protein A-conjugated 10-nm gold particles.
*, labyrinthine channels.
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n
Review
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SCAVENGER ENDOTHELIAL CELLS
cyte pinocytic systems incorporate ultrafiltration filter-slits,
which resemble those of vertebrate glomerulus (19). Orthologs
of the major constituents of the vertebrate kidney podocyte slit
diaphragm, including nephrin and podocin, are expressed in the
Drosophila nephrocyte and form a complex of interacting
proteins that closely mirror the vertebrate slit diaphragm complex, suggesting that the two cell types are evolutionarily
related (170). Thus, some functional elements of invertebrate
nephrocytes evidently evolved into components of the vertebrate kidney glomerulus, while others appear in SECs. Arguments have also been put forward for Rudhira as a molecular
link between pericardial nephrocytes in Drosophila and vertebrate SECs (20). Rudhira is a cytoplasmic WD40 domain
protein suggested to regulate colloid uptake in Drosophila
pericardial nephrocytes (20), where it is expressed in high
levels (while not found in other tissues) (21), while its murine
ortholog is expressed in endothelial precursors during vasculogenesis and angiogenesis (139). The scavenger systems of
invertebrates may, thus, represent waypoints in the molecular
evolution of scavenger processes in vertebrates.
Conclusions: Proposal of a Common Principle of Cellular
Waste Handling
In his account on the waste-clearing cells of animals, Aschoff (3) launched the name RES to denote the cells that were
most actively taking part in the uptake of intravenously administered vital stains (3). He observed that macrophages and
sinusoidal cells of liver and certain other organs took up
massive amounts of vital stains. Over the years that followed
after Aschoff’s work, it became common to think that the RES
consisted of macrophages only. This was partly due to the
misconception that the cells of the RES were professional
phagocytes only and used phagocytosis to clear vital stains
from the circulation. In line with this view, van Furth et al.
The dual-cell principle of waste clearance in the
animal kingdom
A
Cellular uptake of insoluble and soluble
macromolecules is divided into:
Phagocytosis
+
Pinocytosis
and
Clearance of circulating waste
is performed by two very different cell types:
B
Professional phagocytes
Vertebrates:
The macrophage
Invertebrates: The hemocyte
Professional pinocytes
The scavenger endothelial cell
The nephrocyte
Fig. 5. Representation of the dual-cell principle of waste clearance. A: large
particles (⬎0.5 ␮m) are taken up by phagocytosis (23), whereas small particles
(colloids) and soluble waste are taken up by pinocytosis. B: major scavenger
cells that are responsible for the clearance of blood-borne waste are of two very
different types: professional phagocytes (the macrophage in vertebrates and the
hemocyte in invertebrates) and professional pinocytes (the scavenger endothelial cell in vertebrates and the nephrocyte in invertebrates).
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located in the circulating hemolymph (74). Nephrocytes [synonym “athrocytes”; (18)], on the other hand, are highly pinocytic cells tethered to the esophagus (“garland cells”) or to
the heart (“pericardial nephrocytes”) (Fig. 4), and are bathed in
hemolymph (18, 170).
The scavenger function of insect nephrocytes has been
explored for more than 100 years (18). Soluble vital dyes, such
as ammonia carmine and trypan blue, were found to be rapidly
and preferentially taken up by insect pericardial and garland
nephrocytes (118, 121). Morphologically, these nephrocytes
are podocytes, with a filtration slit diaphragm, and deeply
infolded plasma membranes forming labyrinthic channels lined
with numerous coated pits and vesicles (19, 170) (Fig. 4).
However, instead of being passed to a nephric tubule, filtered
material is endocytosed from the side of these channels (20).
Like the vertebrate SEC, the insect nephrocyte is not phagocytic (18, 20).
Clathrin-mediated endocytosis mechanisms have been extensively studied in the fruit fly, Drosophila melanogaster.
However, little is known about endocytosis receptors on
nephrocytes. Recently, Soukup et al. (156) reported the expression of the Lipophorin receptor-1 receptor, a member of the
low-density lipoprotein family, in Drosophila garland and
pericardial nephrocytes. They also demonstrated for the first
time that the serpin-family inhibitor, Necrotic, which controls
a proteolytic cascade, which activates the innate immune
response to fungal and gram-positive bacterial infections, was
cleared from hemolymph via this receptor, and then delivered
to lysosomes for degradation, suggesting an important regulatory role of the nephrocytes in humoral immune responses in
Drosophila.
In addition, nephrocytes avidly sequester soluble tracer molecules, such as horseradish peroxidase, ferritin, juvenile hormone esterase, maleylated BSA (an SR ligand), and acid dyes
(9, 18 –20), suggesting the expression of one or more SRs. We
found that larval Calliphora (blowfly) nephrocytes endocytose
and rapidly degrade formaldehyde-treated albumin. They also
endocytose hyaluronan and AGE-albumin but do not sequester
mannan, suggesting that they do not express a mannose receptor (Smedsrød group, unpublished observations). Fig. 4 shows
the uptake of trypan blue and formaldehyde-treated albumin in
Calliphora larval nephrocytes, and the well-developed endolysosomal network of these cells. The lack of a distinct mannose
receptor (which is found in vertebrates) may reflect the fact that
invertebrate glycoproteins often contain high-mannose groups
(105).
Nephrocytes that strongly resemble insect nephrocytes are
found in ancestors of insects such as Onychophorans (132),
myriapods (127), and spiders (176). Decapod branchial nephrocytes, which are located at the stem of the gill, also show
functional equivalence to the nephrocytes of insects, and are
implicated in the removal from the hemolymph of macromolecules produced during tissue maintenance, growth, and molting (158), as well as vital dyes (112) and virus particles (95).
Pinocytic nephrocytes are also present in bivalve molluscs
(101), and snails (152).
On the basis of their pinocytic scavenging function, we
argue that invertebrate nephrocytes are functionally similar to
the vertebrate SEC. Interestingly, nephrocytes in insects have
been suggested to be evolutionarily related to both vertebrate
glomerular podocytes (170) and endothelial cells (20). Nephro-
Review
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SCAVENGER ENDOTHELIAL CELLS
Perspectives and Significance
The dual-cell principle of waste clearance in the animal
kingdom raises some obvious questions and issues: 1) Any trait
that has been conserved up through evolution must be regarded
as successful and important. Why has it been important to
maintain a dual-cell principle of waste clearance? 2) What is
the ontogenetic origin of the vertebrate SEC? It has been
suggested that the LSEC in mammals is of bone marrow origin
(44). 3) What is the “phylogenetic reason” for “moving” the
population of SECs from the gill vessels in the three phylogenetically oldest vertebrate classes, via heart or kidney in the
bony fishes, and finally to the liver of the four land-based
vertebrate classes? 4) Why do SECs, in general, reside in an
oxygen-poor environment? Is oxygen incompatible with such
waste recycling? 5) What is the exact physical nature of the
ligand binding properties of SEC scavenger receptors? These
need to be studied in more detail to determine to what extent
hydrophobicity and hydrophilicity along with electric charge
(168) determine the ability of these receptors to recognize
material that should be removed from the blood to maintain
homeostasis. 6) Clearly, a number of the substances that are
categorized by immunologists as carrying “danger signals”
(133) are recognized and cleared by the “new” scavenger cells
SECs and nephrocytes. Therefore, why not view the vertebrate
SEC and invertebrate analog nephrocyte as an integral component of the innate immune systems? Studying these fundamental questions will open new avenues to a more complete
understanding of physiology, immunology, and medicine.
ACKNOWLEDGMENTS
This study was supported by The Tromsø Research Foundation (Tromsø,
Norway) and The Ageing and Alzheimer’s Research Foundation, a division of
the Sydney of Medical School Foundation of the University of Sydney.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
Author contributions: K.K.S. and B.S. conception and design of research;
K.K.S., C.C., and B.S. prepared figures; K.K.S., P.M., T.B., C.C., D.G.L.C.,
K.W., and B.S. drafted manuscript; K.K.S., P.M., and B.S. edited and revised
manuscript; K.K.S., P.M., T.B., C.C., D.G.L.C., K.W., and B.S. approved final
version of manuscript.
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