Molecular Immunology 47 (2010) 1650–1660

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Molecular Immunology
journal homepage: www.elsevier.com/locate/molimm

Review

Scavenger receptor CD163, a Jack-of-all-trades and potential

target for cell-directed therapy
Hanne Van Gorp, Peter L. Delputte 1 , Hans J. Nauwynck ∗,1
Department of Virology, Parasitology and Immunology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133,
B-9820 Merelbeke, Belgium

a r t i c l e i n f o a b s t r a c t

Article history: Scavenger receptor CD163 contains nine scavenger receptor cysteine-rich (SRCR) domains and because of
Received 19 January 2010 the presence of this ancient and highly conserved protein motif, CD163 belongs to the SRCR superfamily.
Received in revised form 9 February 2010 Expression of CD163 is restricted to cells of the monocyte/macrophage lineage and is tightly regulated,
Accepted 14 February 2010
with a general tendency of anti-inflammatory signals to induce CD163 synthesis, while pro-inflammatory
Available online 17 March 2010
signals rather seem to downregulate CD163 expression. The first-identified and most-studied function
of CD163 is related to its capacity to bind and internalize haemoglobin–haptoglobin (HbHp) complexes.
Keywords:
Later on, its functional repertoire was expanded, with the identification of CD163 as an erythroblast
Scavenger receptor
CD163
adhesion receptor, a receptor for tumour necrosis factor-like weak inducer of apoptosis (TWEAK), as
Macrophages well as a receptor for distinct pathogens encompassing bacteria and viruses. Interaction of one of these
Ectodomain shedding ligands with CD163 might result in receptor-mediated endocytosis, but might as well trigger a signalling
Targeting cascade leading to the secretion of signalling molecules, which implicates that CD163 also acts as an
immunomodulator. Not only the membrane-bound form of CD163 has an immunomodulating capacity,
but also soluble CD163, which is generated via ectodomain shedding, is able to exert anti-inflammatory
effects. Furthermore, the concentration of this soluble protein is significantly increased under specific
pathological conditions, making it a useful marker protein for certain diseases. Finally, its restricted
expression pattern and potential to internalize make CD163 an attractive candidate as gateway for cell-
directed (immuno)therapy. This review aims to summarize current knowledge on CD163’s biology and its
different biological functions beyond HbHp scavenging, thereby mainly focussing on the more recently
discovered ones. Furthermore, current data supporting the capacity of CD163 to serve as a diagnostic
marker in certain diseases and its potential as a target molecule for cell-directed therapy are surveyed.
© 2010 Elsevier Ltd. All rights reserved.

1. Introduction
Macrophages and their progenitor cells, monocytes, are key
players in the immune system where they fulfil a myriad of func-
tions aided by a vast repertoire of surface molecules. Scavenger
receptor CD163 is one of them and was initially identified as RM3/1
in 1987 (Zwadlo et al., 1987) before receiving its CD number in 1996
(Kishimoto et al., 1997). Different antibodies were raised against
CD163 prior to its cloning and proper characterization, resulting in a
series of different names for the same protein. Besides its most com-
monly used name CD163, this scavenger receptor is also known as
Ki-M8 (Radzun et al., 1987), Ber-MAC3 (Backe et al., 1991), GHI/61
and SM4 (Pulford et al., 1992), RM3/1 (Zwadlo et al., 1987), ED2 anti-
gen (Dijkstra et al., 1985), AM-3K (Komohara et al., 2006; Zeng et al.,
∗ Corresponding author. Tel.: +32 9 264 73 66; fax: +32 9 264 74 95.
E-mail address: Hans.Nauwynck@Ugent.be (H.J. Nauwynck).
1
These authors share senior authorship.
1996), 2A10 (Sanchez et al., 1999), along with p155 (Morganelli and
Guyre, 1988), M130 (Ritter et al., 1999), and haemoglobin scavenger
receptor (HbSR) (Kristiansen et al., 2001).
Only in 2001 however, a function could be attributed to CD163
when this glycoprotein was identified as internalization recep-
tor for haemoglobin–haptoglobin (HbHp) complexes (Kristiansen
et al., 2001). This function of CD163 has been the subject of
extensive investigation, as discussed in several reviews (Ascenzi
et al., 2005; Fabriek et al., 2005; Graversen et al., 2002; Nielsen
and Moestrup, 2009; Nielsen et al., 2010; Onofre et al., 2009;
Schaer et al., 2007; Zuwala-Jagiello, 2006). Meanwhile however,
also other CD163 ligands were described, indicating that CD163
is a multifunctional receptor involved in receptor-mediated endo-
cytosis and in signalling pathways upon interaction with diverse
ligands. This review aims to summarize current knowledge on
CD163’s biology and its different biological functions beyond HbHp
scavenging, thereby mainly focussing on the more recently dis-
covered ones. Furthermore, current data supporting the capacity
of CD163 to serve as a diagnostic marker in certain diseases and

0161-5890/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.molimm.2010.02.008
 H. Van Gorp et al. / Molecular Immunology 47 (2010) 1650–1660
its potential as a target molecule for cell-directed therapy are
surveyed.
2. Classification: scavenger receptor cysteine-rich
superfamily group B
Scavenger receptor (SR) biology originated in 1979, when
Brown and Goldstein explored the uptake of modified low-density
lipoprotein (LDL) by macrophages. At present, the term SR defines a
vast number of glycoproteins involved in the recognition of polyan-
ionic structures of either endogenous (e.g. oxidized or acetylated
LDL) or exogenous (e.g. bacterial lipopolysaccharides (LPS)) ori-
gin. Although functionally related, SR are structurally quite diverse,
containing, among others, collagenous, C-type lectin, leucine-rich
repeat or scavenger receptor cysteine-rich (SRCR) domains. Based
on the multidomain structure, the SR family can be classified into
eight different classes (A–H) (Areschoug and Gordon, 2009; Krieger,
1997; Krieger and Herz, 1994; Murphy et al., 2005; Pluddemann et
al., 2007; Taylor et al., 2005).
The first SR to be cloned was the class A scavenger receptor SR-AI
that is composed of several distinct domains including a C-terminal
SRCR domain (Freeman et al., 1990). At present, this domain has
been found in more than 25 proteins, including CD163, and its pres-
ence is the molecular signature of the so-called SRCR superfamily
(SRCR-SF) as nicely reviewed by Sarrias et al. (2004). Sequences
containing the SRCR domain have been identified in representatives
of diverse animal phyla, ranging from marine sponges (Blumbach
et al., 1998; Pancer et al., 1997) and insects (Gorman et al., 2000),
to avian (Gobel et al., 1996; Iwasaki et al., 2001; Koskinen et al.,
2001), amphibian (Goldberger et al., 1987; Yamada et al., 2000), and
various mammalian species (Aruffo et al., 1991; Holm et al., 2009;
Mackay et al., 1986; Nunes et al., 1995; Polfliet et al., 2006; Takito
et al., 1996). Notwithstanding the structural relationship due to the
presence of this ancient and highly conserved protein motif, there
is, as yet, no unifying biological function for the SRCR-SF (Sarrias et
al., 2004).
The SRCR domain is an extracellular domain consisting of
100–110 amino acid residues (Sarrias et al., 2004). The SRCR-SF can
be divided into two groups (A and B), depending on the number of
cysteine residues present in the SRCR domains, and, consequently,
on the disulphide-bond pattern established. Another distinguishing
feature is the number of exons coding for each SRCR domain. Group
A SRCR domains contain 6 cysteine residues and are encoded by two
exons, whereas those of group B contain 6 or 8 cysteine residues
and are encoded by a single exon. Protein alignment and studies
on the cysteine disulphide linkage pattern of several members of
the SRCR-SF have shown that the relative position of cysteines and
their disulphide bond pattern are well conserved within each SRCR
domain. Thus, according to the usual nomenclature for number-
ing cysteines 1–8 of group B domains, the disulphide pattern of
an SRCR domain is C1–C4, C2–C7, C3–C8, and C5–C6. Cysteines C1
and C4 are absent in group A domains, though always present in
group B domains. Some group B domains lack the C2–C7 bridge
(Resnick et al., 1994; Sarrias et al., 2004). CD163 is composed of
nine type B SRCR domains (SRCR1–9) all containing four disul-
phide bridges except for SRCR8, which lacks the C2–C7 bridge
(Fig. 1).
Members of the group B SRCR-SF are further divided into differ-
ent subgroups based on their structure, sequence homology, and
extracellular domain organization (Gronlund et al., 2000; Sarrias
et al., 2004). The first and most extensively studied subgroup com-
prises CD5 (Jones et al., 1986), CD6 (Aruffo et al., 1991) and Sp␣
(Gebe et al., 1997), which all contain three SRCR domains. The
second subgroup presents SRCR domains that are part of a mul-
tidomain mosaic extracellular region, and includes, among others,
1651
gp-340/SAG/DMBT1 (Holmskov et al., 1997; Ligtenberg et al., 2007;
Mollenhauer et al., 1997). Members are characterized by the pres-
ence of additional domains other than the SRCR domain, such as
epithelial growth factor (EGF) domain, zona pellucida (ZP) domain,
fibronectin domain, etc. The third subgroup contains CD163 (Law
et al., 1993) together with CD163-L1 (Gronlund et al., 2000), WC1
(Mackay et al., 1986; Wijngaard et al., 1992) and SCART (Table 1)
(Holm et al., 2009; Kisielow et al., 2008). They are characterized by
the presence of a long-range repeat of 5 consecutive SRCR domains
with a small linker domain between the second and third SRCR
domain. This long-range repeat is referred to as [b-c-d-e-d] cassette
(Fig. 1). It has been suggested that CD163 emerged from CD163-L1
by gene duplication, and that during this process 3 of the first 6
SRCR domains of CD163-L1 were lost (Gronlund et al., 2000; Stover
et al., 2000).
3. Structure
CD163 is a type I transmembrane protein composed of 9 extra-
cellular consecutive SRCR domains type B, with only SRCR 6 and 7
separated by a proline-serine-threonine rich (PST) polypeptide of
approximately 35 amino acids (Fig. 1). Following the SRCR domains,
a short PST linker domain connects SRCR 9 with a transmembrane
domain and an intracellular cytoplasmic tail. This intracellular tail
is subject to alternative splicing resulting in various CD163 isoforms
that differ in the length of their cytoplasmic tail (Law et al., 1993;
Ritter et al., 1999). The most abundant form has a tail of 49 amino
acids, while the less abundant forms have a tail of 84 or 89 amino
acids. The first 42 amino acids after the membrane-spanning seg-
ment are in common for the three isoforms and this region contains
consensus sequences for phosphorylation with protein kinase C and
creatine kinase. Additional phosphorylation sites are present in the
remaining part of the cytoplasmic tail of the isoforms with 84 amino
acids. Furthermore, the common membrane-proximal region of the
cytoplasmic tail includes a hydrophobic internalization motif of
the type Yxx␾, where ␾ represents a bulky hydrophobic residue
(Nielsen et al., 2006). The observed mass of human CD163 under
non-reducing conditions is 110 kDa, and 130 kDa under reducing
conditions (Pulford et al., 1992). CD163 is extensively glycosylated,
predominantly with N-linked glycans as shown by a reduction in
molecular weight after endoglycosidase F treatment (Fabriek et al.,
2007b; Hogger et al., 1998b).
Recently, the crystallographic structure for a group B SRCR-SF
member was determined. More precisely, the N-terminal (Garza-
Garcia et al., 2008) and the C-terminal (Rodamilans et al., 2007a,b)
SRCR domains of human CD5 were analyzed (Fig. 1). SRCR domains
have a compact fold consisting of a curved six/seven-stranded ␤-
sheet cradling an ␣-helix. The structure core is formed by the
association of helix ␣1 with a curved four-stranded antiparallel
␤-sheet, which includes ␤1, ␤2, ␤4 and ␤7. The three additional
␤-strands (␤3, ␤5, and ␤6) form another antiparallel ␤-sheet at
the bottom of the domain core, as depicted by Rodamilans et
al. (2007b). For comparison with other SRCR domains, the only
information available comes from M2BP (Hohenester et al., 1999),
hepsin (Somoza et al., 2003) and MARCO (Ojala et al., 2007), which
all belong to the group A SRCR-SF. At the sequence level, the only
consistent difference between group A and group B SRCR domains
is the C1–C4 disulphide bond present in group B and absent in group
A. Based on the 3D structures available, this disulphide bond does
not appear to have a major role in shaping the SRCR fold. Main dif-
ferences are observed at the connecting loops, though overall type
A and B SRCR domains share a similar fold with most of the sec-
ondary elements conserved (Garza-Garcia et al., 2008; Rodamilans
et al., 2007b).
1652 H. Van Gorp et al. / Molecular Immunology 47 (2010) 1650–1660

Fig. 1. Schematic representation of SRCR-SF members belonging to the CD163 subgroup, and sequence alignment of the 9 SRCR domains of CD163 and the third SRCR
domain of CD5. (A) CD163 and its closest relatives are type I membrane proteins composed of a variable number of scavenger receptor cysteine-rich (SRCR) domains, and
proline-serine-threonine rich (PST) domains. A common characteristic of these 4 proteins is the presence of a long-range repeat of 5 consecutive SRCR domains with a small
PST linker molecule separating the second and the third SRCR domain. This repeat is referred to as [b-c-d-e-d] cassette. WC1 is represented by the bovine homologue. (B)
CD163 contains 9 type B SRCR domains (SRCR1–9). Type B SRCR domains are characterized by the presence of 6 or 8 cysteine residues, highlighted in grey, resulting in a
typical disulphide linkage pattern appointed as C1–C4, C2–C7, C3–C8, and C5–C6. All 9 SRCR domains contain 4 disulphide bonds, except for SRCR8 that lacks the C2–C7
linkage. The crystal structure was determined for the third SRCR domain of human CD5 (Rodamilans et al., 2007b), which can be used to predict the potential secondary
structure of the CD163 SRCR domains, which are all type B domains as is the case for the CD5 SRCR domains. Furthermore, the ligand-binding pocket (LBP) responsible for
the interaction between several members of the SRCR-SF and their ligands is indicated.

4. Expression and regulation
To date, CD163 has been described in human (Law et al., 1993),
pig (Sanchez et al., 1999), mouse (Schaer et al., 2001), and rat
(Polfliet et al., 2006), but also dog, cattle and monkey homologues
have been identified (Calvert et al., 2007; Sopp et al., 2007; Zwadlo-
Klarwasser et al., 1992). Expression of CD163 is restricted to cells
of the monocyte/macrophage lineage. In tissues, CD163 staining
is predominantly observed on resident tissue macrophages such
as red pulp macrophages in the spleen, Kupffer cells in the liver,
and interstitial and alveolar macrophages in the lungs. In addi-
tion, the CD163 antigen is present on perifollicular and medullary
macrophages in lymph nodes, perifollicular macrophages in the
tonsils, medullary and cortical macrophages in the thymus, and
perivascular and meningeal macrophages in the central ner-
vous system (Van den Heuvel et al., 1999). These mature tissue
macrophages show a substantially higher expression compared to
blood monocytes indicating that CD163 is a differentiation marker
of the macrophage lineage with increased expression along the
macrophage differentiation pathway (Backe et al., 1991; Chamorro
et al., 2005; Sanchez et al., 1999). CD163-positive macrophages
are also found during the healing phase of acute inflammation,
in chronic inflammation and in wound-healing tissue, whereas
freshly infiltrated macrophages are CD163-negative (Verschure et
al., 1989; Zwadlo et al., 1987).
The expression of CD163 is regulated by a variety of factors
(Fig. 3). Genomic analysis of the CD163 promoter region revealed
several binding sites for transcription factors in the 5 flanking
region. These transcription factors have been shown to play an
important role in myeloid-specific gene expression and differen-
tiation. In addition, three putative glucocorticoid receptor binding
sites were identified (Ritter et al., 1999). Indeed, in vitro treatment
of monocytes with the glucocorticoid dexamethasone strongly
induced CD163 expression (Hogger et al., 1998a,b; Morganelli
and Guyre, 1988; Van den Heuvel et al., 1999). Even more, in
vivo administration of glucocorticoids in human volunteers also
resulted in an increase of the CD163-positive monocyte population
(Zwadlo-Klarwasser et al., 1990). Another anti-inflammatory medi-
ator, the cytokine IL-10, also strongly upregulated CD163 mRNA
in monocytes and macrophages, as did the acute phase mediator

Table 1
Group B SRCR-SF members belonging to the CD163 subgroup.

Name Alternative names Expression Form Function References

CD163 M130, RM3/1, haemoglobin Monocytes/macrophages Membrane, soluble HbHp receptor, erythroblast Law et al. (1993) and
scavenger receptor (HbSR), adhesion receptor, virus Kristiansen et al.
p155, etc. receptor, inflammation, (2001)
immunity and host defence
CD163-L1 M160, CD163b Monocytes/macrophages Membrane Inflammation Gronlund et al. (2000)
WC1 T19 ␥␦ T lymphocytes Membrane Reversible G0/G1 cell cycle Mackay et al. (1986)
arrest and Wijngaard et al.
(1992)
SCART ␥␦ T lymphocytes Membrane Kisielow et al. (2008)
and Holm et al. (2009)
 H. Van Gorp et al. / Molecular Immunology 47 (2010) 1650–1660 1653

Fig. 2. Schematic representation of the functional portfolio of CD163. (A) CD163 functions as a scavenger receptor for haemoglobin–haptoglobin (HbHp) complexes. Upon
HbHp complex formation, a neo-epitope is exposed, which interacts with the third SRCR domain of CD163, resulting in signalling events and endocytosis of the receptor–ligand
complex. HbHp-induced signalling triggers production of IL-10, which in turn upregulates production of HO-1 and CD163. Upon endocytosis, the receptor–ligand complex
enters early endosomes where HbHp complexes are released from CD163. The receptor then recycles to the cell surface, while HbHp complexes continue through the
endocytic pathway to end up in lysosomes where the protein moieties of the ligands are degraded. Haem is converted to the overall anti-inflammatory molecules CO, Fe2+ ,
and bilirubin by means of HO-1 and biliverdin reductase in the cytosol. (B) CD163 functions as an erythroblast adhesion receptor, thereby linking developing erythroblasts
to a macrophage. A thirteen amino acid motif in the second SRCR domain of CD163 mediates this interaction. (C) CD163 plays a role as receptor for the cytokine TNF-like
weak inducer of apoptosis (TWEAK). Forty-four putative interaction sites were determined, spread across the SRCR domains, excluding SRCR5. (D) CD163 acts as an innate
immune sensor for bacteria, and upon binding of bacteria to CD163 the production of pro-inflammatory cytokines is induced. The thirteen amino acid motif in SRCR2,
which is responsible for the interaction with erythroblasts, is also involved in the interaction between CD163 and bacteria. (E) CD163 is used by ASFV as an attachment
and internalization receptor to enter macrophages. In addition, CD163 is involved in entry of PRRSV. The virus and CD163 however do not interact at the cell surface, but
only intracellularly in early endosomes where CD163 facilitates PRRSV uncoating. CD163 SRCR domains are coloured in blue, with the domains responsible for interaction
with a specific ligand indicated in purple. Abbreviations: ASFV, African Swine Fever virus; BR, biliverdin reductase; EE, early endosome; HO-1, haem oxygenase-1; LE, late
endosome; Ly, lysosome; PRRSV, porcine reproductive and respiratory syndrome virus.

IL-6 (Buechler et al., 2000; Sulahian et al., 2000). Among 19 iden-
tified IL-10-inducible genes in human monocytes, CD163 in fact
displayed the strongest upregulation (Williams et al., 2002). This is
however not a feature common to all anti-inflammatory cytokines,
since IL-4 and IL-13 were not able to increase CD163 expres-
sion (Buechler et al., 2000; Sulahian et al., 2000; Van den Heuvel
et al., 1999). Interestingly, in contrast to the anti-inflammatory
mediators, pro-inflammatory mediators, like IFN-␥, LPS and TNF-
␣, have been reported to suppress CD163 expression (Buechler
et al., 2000). The reduction observed upon LPS treatment how-
ever, is due to ectodomain shedding (see ‘Soluble CD163 ) and is
observed already at 1 h post treatment, while starting from 24 h
an increase in CD163 surface re-expression is observed (Hintz et
al., 2002; Van den Heuvel et al., 1999; Weaver et al., 2006). It is
of interest to note that activation of cell surface TLRs, like TLR4
activation by LPS, results in increased production of IL-6 and IL-10
followed by upregulation of CD163 expression (Weaver et al., 2006,
2007). So, CD163 expression is tightly regulated by pro- and anti-
inflammatory mediators among others suggesting a role for CD163
in immune responses. Consistent with the expression of CD163 on
mature macrophages in vivo, in vitro differentiation of monocytes
to macrophages by macrophage-colony stimulating factor (M-CSF)
strongly induces CD163 mRNA and protein expression (Buechler
et al., 2000). Intriguingly, when the chemokine CXCL4 was used to
differentiate monocytes into macrophages, CD163 was downreg-
ulated (Gleissner et al., 2010). In addition, when monocytes were
differentiated to dendritic cells by granulocyte macrophage-colony
stimulating factor (GM-CSF) and IL-4, CD163 mRNA transcrip-
tion and protein expression were suppressed (Buechler et al.,
2000). However, low levels of CD163 expression were reported
for monocyte-derived dendritic cells (Sulahian et al., 2000) and
for a small fraction of dendritic cells isolated from the blood
(Maniecki et al., 2006), but the functional significance of this is not
yet clear.
5. Functional role
5.1. CD163 as a receptor for haemoglobin clearance
The most extensively studied function of CD163 is related to the
binding of haemoglobin–haptoglobin (HbHp) complexes, as dis-
covered in 2001 by Kristiansen and co-workers (Fig. 2). Release
of Hb into plasma is a physiological phenomenon associated with
intravascular haemolysis occurring during destruction of senes-
cent or malformed red blood cells. Efficient removal of free Hb
is essential for health because of the oxidative and toxic prop-
erties of the iron-containing haem present in Hb (Ascenzi et al.,
2005; Nielsen et al., 2010). Upon release in the circulation, free
Hb binds to the plasma glycoprotein Hp resulting in one of the
strongest non-covalent interactions observed in plasma (Hwang
and Greer, 1980). Binding of Hb to Hp leads to the exposure of
a neo-epitope interacting with high affinity with the third SRCR
1654 H. Van Gorp et al. / Molecular Immunology 47 (2010) 1650–1660
domain of CD163 in a calcium-dependent manner (Kristiansen
et al., 2001; Madsen et al., 2004). Upon binding to CD163, the
HbHp complexes are internalized by means of the Yxx␾-based
internalization motif common to all three cytoplasmic tail variants
(Nielsen et al., 2006). Among the three variants, the short tail vari-
ant exhibits the highest capacity for ligand endocytosis, probably
due to its more pronounced surface expression compared with the
long tail variants, which are most abundant in intracellular com-
partments (Backe et al., 1991; Nielsen et al., 2006; Van den Heuvel
et al., 1999). Apart from ligand-induced internalization, CD163 also
undergoes constitutive and ligand-independent internalization.
Upon internalization, cargo is delivered to early endosomes and
CD163 recycles to the plasma membrane for a new round of endo-
cytosis (Schaer et al., 2006). Once released, the haem subunit of Hb
is degraded by the rate-limiting haem oxygenase-1 (HO-1) enzyme,
yielding biliverdin, free iron, and the carbon monoxide (CO)
molecule (Nielsen et al., 2010; Philippidis et al., 2004; Schaer et al.,
2008).
5.2. CD163 as an erythroblast adhesion receptor
Already in 1996, the ED2 antigen was reported to mediate ery-
throblast binding (Barbe et al., 1996). Though, only in 2007 when
the ED2 antigen was identified as the rat CD163 surface glyco-
protein, the role of CD163 as erythroblast adhesion molecule was
further explored. CD163 was shown to directly interact with ery-
throblastic cells and a thirteen amino acid motif in the second SRCR
domain of CD163 was identified to mediate this binding. Interac-
tion of this CD163 motif with erythroblasts promotes the growth
and/or survival of these cells (Fabriek et al., 2007b). Apart from
CD163, four other erythroblast adhesion molecules are known on
macrophages (Chasis, 2006; Koury, 2007): vascular cell adhesion
molecule-1 (VCAM-1) (Sadahira et al., 1995), av integrin (Lee et
al., 2006), erythroblast–macrophage protein (EMP) (Hanspal and
Hanspal, 1994), and sialoadhesin (Rughetti et al., 2003). These
adhesion molecules mediate adherence of developing erythrob-
lasts to a central macrophage forming a functional unit termed
erythroblastic island. The interactions enhance erythroblast sur-
vival, proliferation and differentiation during the terminal stages
of erythropoiesis (Chasis, 2006).
5.3. CD163 as a TWEAK receptor
CD163 has recently been proposed as receptor for tumour necro-
sis factor (TNF)-like weak inducer of apoptosis (TWEAK), a secreted
cytokine belonging to the TNF superfamily (Bover et al., 2007;
Chicheportiche et al., 1997). Also fibroblast growth factor inducible
14 (Fn14/TweakR) has been described as TWEAK-binding molecule
(Wiley et al., 2001). Though, cells lacking this receptor were
still TWEAK-sensitive, suggesting the existence of an alternative
TWEAK receptor (Polek et al., 2003). Using a random combinato-
rial peptide library, CD163 was identified as a new TWEAK-binding
protein. Peptide sequences obtained from the screening revealed a
total of 44 putative interaction sites between TWEAK and CD163,
all located in eight of the nine CD163 SRCR domains. Further-
more, HbHp complexes and antibodies recognizing different SRCR
domains of CD163 were all able to inhibit TWEAK binding to CD163.
Together, these data suggest multiple interaction sites between
TWEAK and CD163, including the HbHp recognition site. Upon
binding to CD163-expressing macrophages, TWEAK is internalized
and degraded. CD163 is proposed as scavenger receptor for TWEAK,
preventing TWEAK from exerting its biological functions by seques-
tering it from the environment (Bover et al., 2007; Moreno et al.,
2009).
5.4. CD163 as a pathogen receptor
The most recent discovery concerning the functional portfo-
lio of CD163 proposes a role for this molecule as innate immune
sensor for bacteria. CD163 has been shown to bind both gram-
positive and gram-negative bacteria, and the CD163 motif involved
in this interaction has been shown to be the same as the previ-
ously identified motif involved in erythroblast binding. Expression
of CD163 in monocytic cells promoted bacteria-induced produc-
tion of pro-inflammatory cytokines, like TNF-␣. CD163 is suggested
to act as an innate immune sensor for bacteria and inducer of
local immunity, rather than as a phagocytic receptor (Fabriek et
al., 2009). Interestingly, several other members of the SRCR-SF like
SR-AI (Hampton et al., 1991), gp-340 (Bikker et al., 2002, 2004),
Sp␣ (Sarrias et al., 2005) and CD6 (Sarrias et al., 2007) have previ-
ously been demonstrated to mediate bacterial binding. It remains
however to be analyzed whether pathogen scavenging is a general
property shared by all members of the SRCR-SF or only by a selected
group of members.
Several pathogens have evolved mechanisms to evade recep-
tor recognition or to exploit these receptors for their own benefit,
mainly to enter their host cell. Two viruses, namely the African
swine fever virus (ASFV) and the porcine reproductive and res-
piratory syndrome virus (PRRSV) have been shown to (mis)use
CD163 during entry into their target cells belonging to the mono-
cyte/macrophage lineage (Sanchez-Torres et al., 2003; Van Gorp
et al., 2008). For both viruses, expression of CD163 was shown
to correlate with susceptibility to virus infection (Patton et al.,
2009; Sanchez-Torres et al., 2003). The exact role of CD163 during
infection of both viruses however seems to differ since CD163 is
proposed to function as an attachment and internalization recep-
tor for ASFV (Sanchez-Torres et al., 2003), while for PRRSV data
sustain a role for CD163 during virus uncoating (Van Gorp et al.,
2008, 2009). Analysis of the interaction between PRRSV and CD163
revealed that the cytoplasmic tail containing the internalization
motif is dispensable for PRRSV infection, as are the 4 N-terminal
SRCR domains. The essential domains are more centrally located
with a key role for SRCR domain 5, but also other SRCR domains
and the 2 PST domains are required (Van Gorp et al., 2010). So far,
no biological role has been attributed to these domains as other lig-
ands were shown to interact with SRCR domain 2 or 3 (Fabriek et al.,
2007b, 2009; Madsen et al., 2004). The interaction between CD163
and bacteria or erythroblasts could be pinpointed to an 11–13
amino acid motif within the second SRCR domain. This motif was
previously localized to a putative ligand-binding pocket of the SRCR
domain of M2BP and has been shown to mediate ligand-binding for
several other members of the SRCR-SF, including gp-340, MARCO,
and thus also CD163 (Bikker et al., 2004; Elomaa et al., 1998). The
potential of this motif to mediate cell and pathogen recognition is
further supported by the prediction that this motif is localized in a
short loop extending from the surface of the SRCR domain (Fabriek
et al., 2009; Rodamilans et al., 2007b). Whether or not this motif
is involved in the interaction between CD163 and ASFV or PRRSV
remains to be discovered. So far, only one other member of the
SRCR-SF has been related to virus infection, namely gp-340. The
N-terminal SRCR domain of gp-340 has been implicated in bind-
ing with HIV viral glycoprotein gp-120 (Wu et al., 2006). Yet, the
functional relevance of this interaction is still a matter of debate
since inhibition (Wu et al., 2006) as well as promotion (Cannon et
al., 2008; Stoddard et al., 2007) of HIV infection has been described.
5.5. CD163 as immunomodulator
Different populations of activated macrophages can be dis-
tinguished based on activation signals, secretory products, and
biological markers. Whereas classical activation of macrophages
 H. Van Gorp et al. / Molecular Immunology 47 (2010) 1650–1660 1655

Fig. 3. Regulation of CD163 expression and shedding. (A) CD163 expression is tightly regulated. Overall, anti-inflammatory signals seem to induce CD163 synthesis, while pro-
inflammatory signals seem to downregulate CD163 expression. Differentiation into macrophages via M-CSF results in higher CD163 expression levels, while differentiation
into dendritic cells via GM-CSF and IL-4 results in lower CD163 expression levels. (B) Several signals are able to induce protease-dependent cleavage of the extracellular part
of CD163, which results in the release of soluble CD163 (sCD163). Treatment with LPS results in shedding of sCD163, and consequently initial downregulation of cell surface
CD163. Over time however, CD163 cell surface expression is restored to similar or even higher levels compared to the situation prior to LPS treatment. The soluble form of
CD163 has anti-inflammatory properties and is used as a marker protein for certain pathological conditions.

by IFN-␥ and TNF-␣ results in decreased expression of CD163
(Buechler et al., 2000), elevated levels of CD163 expression are
induced by glucocorticoids, IL-6, and IL-10 (Buechler et al., 2000;
Hogger et al., 1998a; Sulahian et al., 2000) resulting in a distinct
population of cells called the ‘alternatively activated macrophages’.
The anti-inflammatory IL-10 is one of the typical cytokines pro-
duced by alternatively activated macrophages, which fail to make
NO, are not efficient in antigen presentation and inhibit T lympho-
cyte proliferation. They are however implicated in wound-healing,
angiogenesis, and protection of the host from an overwhelming
inflammatory response. Thus, alternatively activated macrophages
tend to serve more a regulatory and recovery function than
the effector killing functions associated with classically activated
macrophages (Mosser, 2003). Early immunohistochemical studies
support the involvement of CD163-positive macrophages in the
late downregulatory phase of acute inflammation (Zwadlo et al.,
1987) and in chronic inflammation (Topoll et al., 1988).
CD163 is well known as receptor for HbHp complexes. Inter-
estingly, the metabolites released upon HbHp degradation, more
precisely bilirubin, free iron, and CO, all have strong anti-oxidative
and anti-inflammatory effects (Otterbein et al., 2003). A key
molecule in this process is the HO-1 enzyme converting haem
into its metabolites (Soares and Bach, 2009). In addition, bind-
ing of HbHp to CD163 elicits a direct anti-inflammatory effect
via the secretion of IL-10 (Philippidis et al., 2004), which in turn
upregulates CD163 expression thereby amplifying HbHp scaveng-
ing via a positive feedback loop (Buechler et al., 2000; Sulahian et
al., 2000). Furthermore, binding of HbHp also induces expression
of the rate-limiting enzyme HO-1 via an IL-10 autocrine mecha-
nism (Philippidis et al., 2004). CD163-positive macrophages thus
efficiently metabolize toxic haem via CD163 binding and HO-1
degradation, and meanwhile exert anti-inflammatory effects via
the release of IL-10 and haem metabolites.
Besides mediating anti-inflammatory effects, CD163 signalling
has also been implicated in the production of pro-inflammatory
cytokines. Cross-linking of CD163 with CD163-specific monoclonal
antibodies induced secretion of NO, IL-1␤, IL-6, and TNF-␣ (Polfliet
et al., 2006; Van den Heuvel et al., 1999). IL-1␤ and TNF-␣ are pro-
inflammatory cytokines, while NO and IL-6 exert both pro- and
anti-inflammatory effects. Furthermore, also bacteria elicit pro-
duction of pro-inflammatory cytokines upon binding with CD163
(Fabriek et al., 2009). All together, CD163 appears as a two-
faced immunomodulator, able to stimulate as well as suppress the
immune response.
6. Soluble CD163 (sCD163)
CD163 is not only present as a membrane-bound form, but
can also be detected in high concentrations as soluble protein in
plasma (Fig. 3) (Droste et al., 1999; Moller et al., 2002c). Rather
than being the product of alternative splicing, soluble CD163
(sCD163) is actively shed from the plasma membrane by metal-
loproteinases, though the responsible metalloproteinase and the
cleavage site remain elusive so far (Droste et al., 1999; Hintz et
al., 2002; Matsushita et al., 2002; Moller et al., 2009). The result-
ing soluble protein displays an electrophoretic mobility similar to
that of a recombinant soluble protein composed of all nine SRCR
domains, suggesting that CD163 is cleaved near the plasma mem-
brane (Moller et al., 2002c). Later on, mass spectrometry was used
showing that sCD163 indeed covers more than 94% of the extracel-
lular part of CD163 (Moller et al., 2009). In vitro, shedding of CD163
is induced in response to phorbol 13-myristate 12-acetate treat-
ment (PMA; also known as 12-O-tetradecanoylphorbol-13-acetate
(TPA)) and acts via a protein kinase C-dependent mechanism
(Droste et al., 1999). Phorbol esters are well known to induce
ectodomain shedding of various transmembrane molecules (Dello
Sbarba and Rovida, 2002), though they are nonphysiological com-
pounds that cannot account for the activation of shedding in vivo.
Furthermore, endotoxins, like LPS, are potent inducers of CD163
shedding both in vitro and in vivo, and this via activation of cell
surface TLRs (Hintz et al., 2002; Weaver et al., 2006). Interestingly,
induced shedding of CD163 is followed by recovery and induction
of surface CD163 to similar or even higher levels than observed in
untreated controls (Hintz et al., 2002; Pulford et al., 1992; Weaver
et al., 2007). Another natural stimulus triggering CD163 shedding is
found in immune complexes cross-linking Fc␥ receptors (Sulahian
et al., 2004). Furthermore, oxidative stress mediators, often present
under inflammatory conditions, were also identified as stimuli for
CD163 ectodomain shedding (Timmermann and Hogger, 2005).
Ectodomain shedding is observed for a wide variety of molecules
including adhesion molecules (e.g. ICAM-1), mediators of apopto-
sis (e.g. Fas ligand), receptors (e.g. CD14), cytokines (e.g. TNF-␣),
growth factors (e.g. EGF), etc. (Cauwe et al., 2007; Garton et
al., 2006). So far, only for one other member of the SRCR-SF,
1656 H. Van Gorp et al. / Molecular Immunology 47 (2010) 1650–1660
more precisely CD5, the process of ectodomain shedding has
been described (Calvo et al., 1999). Ectodomain shedding repre-
sents a post-translational mechanism regulating cellular responses
and interactions at multiple levels, like the release of cytokines
expressed as pro-forms generating soluble mediators, or reduction
of the density of a receptor or adhesion molecule and production of
soluble competitors for their own ligands. For CD163 however, little
is known about the biological functions of its soluble form. Bind-
ing of sCD163 to HbHp complexes has been suggested to reduce
cellular iron uptake, thereby limiting pathogen access to free Hb
and inhibiting growth of intracellular pathogens (Madsen et al.,
2004; Weaver et al., 2006). A recent study however showed that
HbHp complexes preferentially bind to the membrane-bound form
of CD163, and that sCD163 is normally not in complex with HbHp
complexes in the plasma. This is presumably due to the di- or multi-
valent nature of HbHp complexes in terms of CD163 binding (Moller
et al., 2009). Furthermore, a potential direct anti-inflammatory
effect of sCD163 was described, showing inhibition of T lympho-
cyte activation and proliferation upon interaction with sCD163
(Hogger and Sorg, 2001). This phenomenon could not be observed
for membrane-bound CD163, clearly showing distinct functions for
the soluble and membrane-bound form of CD163 (Frings et al.,
2002). Interaction between sCD163 and T lymphocytes is medi-
ated by non-muscle myosin heavy chain in T lymphocytes, though
further research is needed to clarify the consequences of this inter-
action (Timmermann et al., 2004).
The concentration of sCD163 in serum or plasma from healthy
individuals is relatively high, with an average of 2 mg/l, and can
readily be measured using an ELISA (Moller et al., 2002b,c, 2003;
Perez et al., 2008; Sulahian et al., 2001). Intriguingly, sCD163 lev-
els are increased many-fold during various pathological conditions
and its use as marker protein monitoring macrophage activity
is explored for an increasing number of diseases. Gaucher’s dis-
ease is an inherited lysosomal storage disorder characterized by
excessive accumulation of macrophages and patients exhibit highly
increased levels of sCD163. Besides having a diagnostic value in
screening for Gaucher’s disease, sCD163 also correlates with clini-
cal manifestations and might be useful in monitoring disease course
and response to treatment (Moller et al., 2004). Overwhelming
macrophage activity is also observed in patients with the reactive
haemophagocytic syndrome (RHS), though differentiation from
other systemic inflammatory conditions long proved a challeng-
ing task since none of the used markers, like TNF-␣ and ferritin,
is a specific indicator of macrophage activity. Recently, sCD163
was suggested as a potentially useful marker for RHS due to its
macrophage-specific expression pattern and highly increased lev-
els, up to 20 times, in RHS patients. Furthermore, a close correlation
was revealed between sCD163 levels and clinical disease activity
(Schaer et al., 2005). sCD163 has further been revealed as a promis-
ing marker molecule for macrophage activation in diseases and
pathological conditions such as sepsis (Moller et al., 2002c, 2006),
liver disease (Hiraoka et al., 2005a,b; Moller et al., 2007), autoim-
mune disorders (Baeten et al., 2004; Bleesing et al., 2007; De Rycke
et al., 2005), multiple sclerosis (Fabriek et al., 2007a), and malaria
(Kusi et al., 2008).
7. CD163 as target molecule for cell-directed
(immuno)therapy
Apart from being a useful tool in the diagnosis of certain dis-
eases, CD163 also appears as an interesting candidate for medical
therapy. Its restricted expression pattern and potential to func-
tion as an endocytic receptor make CD163 an attractive target
molecule for cell-directed therapy as already posted by Graversen
et al. (2002). CD163 is selectively expressed on subpopulations
of macrophages and monocytes and expression is even upregu-
lated under inflammatory conditions like in rheumathoid arthritis.
In addition to treatment of inflammatory diseases, other appli-
cations are apparent including treatment of infectious diseases
in which macrophages function as hiding place for intracellu-
lar pathogens like Mycobacterium tuberculosis (McKinney et al.,
2000). Furthermore, macrophages have the capacity to function
as antigen-presenting cells, and have been found associated with
tumours (Allavena et al., 2008), providing additional applications.
CD163 also has an immunomodulating potential that can be tar-
geted, thereby either stimulating or repressing the immune system
depending on the ligand and the cellular micro-environment. Not
only a multitude of applications can be imagined, also several
options are available to specifically target CD163, including the dif-
ferent CD163 ligands and CD163-specific antibodies. Since CD163
undergoes constitutive internalization, it is to be expected that any
substance bound to it will be transferred across the plasma mem-
brane. Concerns about the efficiency of CD163-directed therapy
might however arise because of the existence of a soluble form of
CD163. The soluble form is naturally present at high concentrations
in serum and levels are even significantly upregulated under vari-
ous pathological conditions (Droste et al., 1999; Moller et al., 2002a,
2004; Schaer et al., 2005). This soluble protein might capture the
CD163-specific therapeutics before they can reach the macrophage,
as shown for CD97 (de Groot et al., 2009), thereby interfering with
efficient delivery and increasing off-target side effects. This knowl-
edge emphasizes the importance of careful examination of the
expression profile of the membrane-bound as well as the solu-
ble receptor, as exemplified by a study exploring the potential of
CD163 as target for patients with acute myeloid leukemia (AML).
It was shown that there is no increase in sCD163 concentration
in patients whose leukemic blasts displayed high surface CD163
expression, supporting the potential of CD163 as target molecule
in the treatment of AML (Bachli et al., 2006). Furthermore, even
if there is sCD163, this does not necessarily means that sCD163
serves as a sink for CD163-specific therapeutics. At least for HbHp
complexes it has been shown that they preferentially interact with
membrane-bound CD163 instead of sCD163 (Moller et al., 2009).
All together, further research is imperative to circumvent poten-
tial pitfalls and to fully explore the potential of CD163 as target for
cell-directed therapy.
8. Concluding Remarks
Scavenger receptor CD163 manifests itself as a multifunctional
molecule fulfilling essential homeostatic functions in diverse bio-
logical processes, with multiple ligands that are able to engage
CD163. The outcome of these interactions however seems to be
ligand-specific and diverse pathways might be set in motion.
Binding of HbHp complexes not only triggers receptor-mediated
endocytosis, but also activates a signalling cascade resulting in
the production of anti-inflammatory molecules. Other ligands
however, like bacteria, elicit a pro-inflammatory instead of an anti-
inflammatory response. Furthermore, bacteria are not internalized
upon interaction with CD163, in contrast to HbHp complexes and
TWEAK. Currently however, little is known about the regulatory
mechanisms influencing the outcome of the ligand-CD163 inter-
actions. What is known so far is that different CD163 domains
are implicated in the interaction between CD163 and HbHp com-
plexes or bacteria. To what extent these interacting SRCR domains
of CD163 are a determining factor in the outcome of the interaction
remains elusive, as are the signalling pathways triggered. There-
fore, more profound knowledge on the events following ligand
binding to CD163 is required, not only to further our understanding
of fundamental CD163 biology, but also because it is a prerequisite
in the development of CD163-specific therapeutics.
 H. Van Gorp et al. / Molecular Immunology 47 (2010) 1650–1660
CD163 is reported to function as an innate immune sensor for
bacteria, thereby protecting the host. For other pathogens however,
like the porcine viruses ASFV and PRRSV, CD163 serves as a por-
tal that allows infection of their target cells. Interestingly, CD163
seems to contribute in a different manner during entry of both
viruses. For ASFV, CD163 is suggested to function as an attachment
and internalization receptor, while for PRRSV CD163 is proposed
to act at a post-internalization stage, more precisely during virus
disassembly. Indicative of this new role of CD163 is that the cyto-
plasmic tail of CD163 containing the internalization motif is not
required for PRRSV infection, while it is essential for uptake of
HbHp complexes, sustaining the functional flexibility of CD163.
Furthermore, the CD163 domains essential for PRRSV infection are
different from the ones implicated in the interactions with other
ligands and are more centrally located. Still, the precise molecular
mechanism underlying the CD163-dependent uncoating of PRRSV
remains to be elucidated. Intriguingly, the CD163 ancestor, CD163-
L1, is not able to replace CD163 functionality during PRRSV entry
(Van Gorp et al., 2010), although CD163 originates from CD163-L1
and both proteins are structurally much alike. Therefore, it seems
intriguing to explore the functional repertoire of CD163-L1 as well
as the potential functional redundancy between CD163 and CD163-
L1 to accomplish a holistic picture of these closely related scavenger
receptors.
Acknowledgements
The authors would like to thank Wander Van Breedam for fruit-
ful discussions and critical reading of the manuscript. This work was
supported by the Industrial Research Fund (IOF) of Ghent Univer-
sity and by the European Union (Seventh Framework Programme,
Project No. 245141, coordinated by Dr. H. Nauwynck).
The authors declare that they have no conflict of interest.
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