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Tobias F. Fischer and Annette G. Beck-Sickinger*
Chemerin –exploring a versatile adipokine
https://doi.org/10.1515/hsz-2021-0409
Received November 6, 2021; accepted December 23, 2021;
published online January 18, 2022
Abstract: Chemerin is a small chemotactic protein and a key
player in initiating the early immune response. As an adi-
pokine,chemerin is also involved in energy homeostasis and
the regulation of reproductive functions. Secretedas inactive
prochemerin, it relies on proteolytic activation by serine
proteases to exert biological activity. Chemerin binds to
three distinct G protein-coupled receptors (GPCR), namely
chemokine-like receptor 1 (CMKLR1, recently named chem-
erin
1
), G protein-coupled receptor 1 (GPR1, recently named
chemerin
2
), and CC-motif chemokine receptor-like 2 (CCRL2).
Only CMKLR1 displays conventional G protein signaling,
while GPR1 only recruits arrestin in response to ligand
stimulation, and no CCRL2-mediated signaling events have
been described to date. However, GPR1 undergoes consti-
tutive endocytosis, making thisreceptor perfectly adaptedas
decoy receptor. Here, we discuss expression pattern, acti-
vation, and receptor binding of chemerin. Moreover, we re-
view the current literature regarding the involvement of
chemerin in cancer and several obesity-related diseases, as
well as recent developments in therapeutic targeting of the
chemerin system.
Keywords: adipose tissue; cytokine; immunity; inflam-
mation; obesity.
Expression and tissue distribution
of chemerin
In 1997, Chandraratna and colleagues reported the identi-
fication of a novel gene in psoriatic skin lesions. Expression
of this gene was upregulated in response to treatment
with the anti-psoriatic retinoic acid tazarotene, and it was
therefore named tazarotene-induced gene 2 (TIG2) or reti-
noid acid responder protein 2 (RARRES2) (Nagpal et al.
1997). After identifying the TIG2 gene product as the nat-
ural ligand of CMKLR1, Wittamer et al. (2003) named the
protein chemerin.
Chemerin is expressed as a biologically inactive pro-
form named preprochemerin, consisting of 163 amino
acids. Upon truncation of the 20 amino acid N-terminal
signal peptide, it is secreted as prochemerin, which is the
main form of chemerin found in the circulation (Chang
et al. 2016; Wittamer et al. 2003).
The highest expression of chemerin mRNA in mice has
been detected in the liver, which is most likely the main
source of circulating chemerin in lean individuals (Banas
et al. 2015; Ernst et al. 2010; Weigert et al. 2010). Chemerin
is also found in the skin, where it is expressed in the
epidermis (Banas et al. 2015; Schultz et al. 2013), and in the
lung (Luangsay et al. 2009). Articular chondrocytes, a
specialized cell type found in joints, have been demon-
strated to express chemerin (Berg et al. 2010), and in-
creased chemerin levels are found in the synovial fluid of
inflamed joints (Wittamer et al. 2003). Moreover, chemerin
mRNA is found in the uterus, ovary, testes, colon, and
spleen of mice (Luangsay et al. 2009).
On the protein level, chemerin displays the highest
expression in white adipose tissue (Banas et al. 2015).
Expression of chemerin in murine adipose tissue has been
confirmed by Roh et al. (2007), who additionally demon-
strated that the level of chemerin expressed by the murine
pre-adipocyte cell line 3T3-L1 increases during their dif-
ferentiation into mature adipocytes. Using murine mesen-
chymal stromal cell-derived adipocytes, Dranse et al. (2016)
found the same results, showing increasing expression of
chemerin over the course of differentiation. Consequently,
chemerin is also found at high concentrations in human
adipose tissue, as demonstrated by Chang et al. (2016).
Structure and proteolytic
processing of chemerin
Chemerin is a protein without any known close sequence
homolog, and no crystal structure has been published to
date. Structurally, the closest homolog as determined by
*Corresponding author: Annette G. Beck-Sickinger, Institute of
Biochemistry, University of Leipzig, Brüderstraße 34, D-04103 Leipzig,
Germany, E-mail: abeck-sickinger@uni-leipzig.de.
https://orcid.org/0000-0003-4560-8020
Tobias F. Fischer, Institute of Biochemistry, University of Leipzig,
Brüderstraße 34, D-04103 Leipzig, Germany
Biol. Chem. 2022; aop
fold recognition is the cathelin-like domain of the human
cathelicidin LL-37, a member of the innate immune system
(Kelley et al. 2015; Pazgier et al. 2013). LL-37 acts as cationic
antimicrobial protein, and is chemotactic for monocytes,
mast cells, neutrophils, and T-cells (Zanetti 2004). Both
chemerin and LL-37 share structural homology with
cystatins, a large family of cysteine protease inhibitors
(Rawlings and Barrett 1990).
The first structural characterization of chemerin was
an NMR assignment by Allen et al. (2007). They predicted a
central β-sheet flanked by two α-helices, with an unstruc-
tured, flexible C-terminus, and postulated the presence of
three disulfide bridges. Employing a combination of ho-
mology modeling and de novo protein structure prediction,
Schultz et al. (2013) constructed a model of prochemerin
(Figure 1), which closely matches the results from these
NMR studies and is in close agreement with the recently
published structural model by AlphaFold (Jumper et al.
2021).
Prochemerin relies on C-terminal protease cleavage to
exert biological functions through the chemokine-like re-
ceptor 1 (CMKLR1). Incorporating mutagenesis data with
computational modeling, Schultz et al. (2013) showed that
this protease-mediated activation cleaves off a C-terminal
helical segment, resulting in a flexible C-terminus. The
most active chemerin species terminate at S157 or F156 and
accordingly are named ChemS157 or ChemF156, respec-
tively (Schultz et al. 2013). Short peptides derived from the
C-termini of these two species are sufficient to trigger
activation at the CMKLR1 and the second chemerin receptor
GPR1 (de Henau et al. 2016; Wittamer et al. 2004). A slightly
longer chemerin form, ChemK158, is significantly less
active at the CMKLR1, while chemerin species lacking F156,
i.e., ChemA155 and shorter variants, are completely inac-
tive (Wittamer et al. 2004; Yamaguchi et al. 2011). Inter-
estingly, ChemA155 even shows weak antagonism at
CMKLR1, highlighting the complex interplay between the
different chemerin species (Yamaguchi et al. 2011).
Several proteases are known that can process proche-
merin, many of which are present in blood plasma: Two
enzymes of the coagulation cascades, factors Xa and VIIa
both generate active chemerin from prochemerin, offering a
link between tissue damage and chemerin activation (Zabel
et al. 2005). Plasmin, an enzyme of the fibrinolytic cascade,
generates the biologically inactive ChemK158, which can
then be converted to active ChemS157 bycarboxypeptidase
N, a constitutively active serine protease (Du et al. 2009).
These results suggest that active chemerin is generated
during the process of blood clotting and de-clotting after
blood vessel damage. Apart from these proteases, immune
cell-derived enzymes can activate and de-activate chem-
erin: Two proteases released from neutrophils, elastase and
cathepsin G, can generate active ChemS157 from proche-
merin, while the neutrophil-derived enzyme proteinase 3
converts prochemerin to inactive ChemA155 (Guillabert
et al. 2008; Wittamer et al. 2005; Zabel et al. 2005). Addi-
tionally, chymase, an enzyme secreted by mast cells, in-
activates ChemS157 by cleavage of the two ultimate amino
acids, generating ChemF154 (Guillabert et al. 2008). Next to
these plasma and immune cell-derived proteases, kalli-
krein (KLK) 7 is the only tissue-specific enzyme reported
to process chemerin. Predominantly found in the skin,
it converts prochemerin to active ChemF156 (Schultz
et al. 2013).
Figure 1: Structure and sequence of human chemerin.
(A) The homology model of human chemerinS157 displays a central β-sheet flanked by two α-helices (Schultz et al. 2013). The three putative
disulfide bridges are highlighted as yellow spheres. (B) Primary sequence of human preprochemerin, the N-terminal signal peptide is
highlighted with gray background, disulfide bridges are indicated by square brackets. The C-terminal peptide chemerin-9 is highlighted.
2T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine
While prochemerin is by far the most abundant
chemerin form in blood plasma, the active ChemS157 is
dominant in adipose tissue (Chang et al. 2016). This may be
due to the co-expression of prochemerin and the chemerin-
activating enzymes elastase and tryptase by adipocytes, as
demonstrated by Parlee et al. (2012). An overview over post-
secretary processing of chemerin is given in Figure 2 and by
Mattern et al. (2014).
Taken together, these results demonstrate that inac-
tive prochemerin is permanently circulating in the blood-
stream, waiting to be activated upon tissue damage or
inflammation. Skin and adipose tissue may play a special
role, as they can be expected to dispose active chemerin
species independent of triggering events.
The chemerin receptors
Chemerin binds to three distinct G protein-coupled re-
ceptors (GPCR), and each of these chemerin receptors has
a distinct pharmacological profile. CMKLR1, recently also
named chemerin receptor 1 (chemerin
1
) was the first re-
ceptor reported to bind to chemerin in 2003 (Kennedy and
Davenport 2018; Wittamer et al. 2003). G protein-coupled
receptor 1 (GPR1), the closest sequence homolog of CMKLR1,
and recently named chemerin receptor 2 (chemerin
2
) was
identified as a receptor for chemerin shortly after (Barnea
et al. 2008; Kennedy and Davenport 2018). CMKLR1 and
GPR1 share the highest sequence identities with the
formyl peptide receptors (Figure 3A), pattern-recognizing
G
i
-coupled receptors that are activated by a wide range of
formylated bacterial peptides and are involved in host de-
fense (Chen et al.; Weiß and Kretschmer 2018; Zhuang
et al.). However, in an in-depth phylogenetic analysis, Fre-
drikson et al.grouped GPR1 and CMKLR1 with the receptors
for the complement 5a (C5a) anaphylatoxin (Fredriksson
et al. 2003). C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2,
formerly C5L2) play an important role in complement-
mediated innate immunity (Pandey et al. 2020) and show
functional similarities to GPR1 and CMKLR1, which will be
discussed in the following sections.
In contrast to CMKLR1 and GPR1, CC-motif chemokine
receptor-like 2 (CCRL2), the third chemerin receptor, is
grouped with the chemokine receptors (Figure 3A) (Fre-
driksson et al. 2003). However, no chemokine ligands for
CCRL2 have been described to date, making chemerin the
only known ligand for CCRL2 so far (Zabel et al. 2008).
CMKLR1
CMKLR1 or chemerin
1
is a receptor expressed by several
types of immune cells: Macrophages and dendritic
cells express CMKLR1 and display CMKLR1-dependent
migration towards increasing concentrations of chemerin
(Wittamer et al. 2003). Natural killer (NK) cells also express
CMKLR1 and decreased expression of this receptor has
been associated with reduced migration towards chemerin
(Parolini et al. 2007). Apart from these immune cells,
CMKLR1 expression has also been detected in human and
murine adipocytes, and RNA-targeted knockdown of this
receptor resulted in an impaired differentiation of 3T3-L1
Figure 2: Proteolytic activation and deactivation of chemerin by immune cell-derived (mast cell and neutrophil-secreted), plasma, or tissue-
specific proteases.
Differently processed chemerin species vary in the positions of their respective C-termini.
T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine 3
cells into mature adipocytes (Goralski et al. 2007). More-
over, CMKLR1 is expressed by primary human hepatocytes
and vascular endothelial cells (Döcke et al. 2013; Kennedy
et al. 2016).
Studies with CMKLR1 knock-out mice came to con-
flicting results: Rouger et al. (2013) describe a higher fat
mass and body weight, but unaltered glucose tolerance
for CMKLR1−/−mice compared to the control group. In
contrast, Ernst et al. (2012) report a lower food intake and
body weight, combined with lower glucose tolerance and
insulin secretion for CMKLR1−/−mice compared to the
control group, independent of diet. Moreover, Ernst et al.
(2012) describe decreased levels of the pro-inflammatory
cytokines tumor necrosis factor (TNF) αand interleukin (IL)
6 in white adipose tissue (WAT) of CMKLR1−/−mice fed a
high-fat diet compared to the control group, which is not
confirmed by the results by Rouger et al. (2013).
Chemerin was independently discovered as a natural
ligand for CMKLR1 by two different groups (Meder et al.
2003; Wittamer et al. 2003): Wittamer et al. (2003) were the
first to engage in detailed structure-activity studies of this
interaction, revealing that the agonistic properties of
chemerin are preserved in its C-terminus. Employing
radioligand-binding and Ca2+mobilization assays, they
demonstrated that the C-terminal aromatic residues, and
especially F156, are crucial for binding to and activation
of CMKLR1 (Wittamer et al. 2004). They identified the
C-terminal nonapeptide as the minimal activation motif
and named it chemerin-9. This peptide has since been used
since then as a tool compound for numerous studies
(Bandholtz et al. 2012; de Henau et al. 2016; Peyrassol et al.
2016; Shimamura et al. 2009; Tu et al. 2020). Recently, we
further characterized the interaction between chemerin-9
and CMKLR1 and demonstrated that chemerin-9 interacts
with several conserved aromatic residues in the extracel-
lular loops of CMKLR1, folding into a hairpin conformation
to induce receptor activation (Fischer et al. 2021c). Thus,
the terminal phenylalanine in chemerin-9 (F8, corre-
sponding to F156 in the full-length protein) binds to a hy-
drophobic patch in the second extracellular loop (ECL2) of
CMKLR1, while F6 (corresponding to F154 in the full-length
protein) interacts with Y2.63 and Y2.68 in the extracellular
domain of transmembrane helix 2 and ECL1, respectively
(nomenclature according to Ballesteros and Weinstein
[1995]). This results in a binding mode where both termini
of the ligand face the extracellular solvent, while the cen-
tral stretch of amino acids reaches deep down into the
transmembrane bundle (Figure 4).
Based on experiments using nanobodies directed
against CMKLR1, Peyrassol et al. (2016) hypothesized that
chemerin binds to CMKLR1 similar to the two-step binding
model postulated for chemokines (Thiele and Rosenkilde
2014). According to this hypothesis, the cystatin motif of
chemerin interacts with the extracellular parts of the re-
ceptor, positioning the chemerin C-terminus in the trans-
membrane bundle to trigger activation of the receptor. This
Figure 3: Chemerin binds to the three GPCR CMKLR1, GPR1, and CCRL2.
(A) Phylogenetic tree using a sequence alignment of selected human protein, peptide, and fatty acid receptors from the γbranch of rhodopsin-
like GPCR generated by GPCRdb. The dendrogram was calculated using the Clustal Omega “simple phylogeny”tool and visualized in R using
the ggtree library (Yu 2020). (B) Activation of CMKLR1 and GPR1 is mediated through the chemerin C-terminus, which does not bind to CCRL2.
Instead, chemerin might bind to CCRL2 exclusively through the cystatin domain.
4T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine
binding mode could be similar to the interaction of C5aR1
with its ligand C5a (Siciliano et al. 1994).
The anti-inflammatory lipid mediator resolvin E1
(RvE1) has been described as an additional ligand for
CMKLR1 (Arita et al. 2005; Ohira et al. 2010). However,
while an independent group has reported RvE1-induced
arrestin 3 recruitment (Krishnamoorthy et al. 2010), others
could not confirm binding of RvE1 to CMKLR1 (Kennedy
and Davenport 2018; Luangsay et al. 2009). Unable to
reproduce RvE1 binding to CMKLR1, Bondue et al. (2011)
suggest that instead of CMKLR1 the related leukotriene B4
receptor 1 (BLTR1) is the actual target of RvE1.
CMKLR1 couples to Gα
i
proteins, which inhibit the
synthesis of cyclic adenosine monophosphate (cAMP) by
adenylyl cyclases (Baltoumas et al. 2013; de Henau et al.
2016). Moreover, stimulation with chemerin leads to the
recruitment of arrestin 3 and subsequent internalization
of the receptor (de Henau et al. 2016; Zhou et al. 2014). In
inflammatory macrophages, this internalization is regu-
lated by G protein-coupled receptor kinase (GRK) 6 and
arrestin 3 (Serafin et al. 2019). Consequently, GRK6 and
arrestin 3-deficient macrophages display prolonged
CMKLR1-signaling and increased migration towards
increasing concentrations of chemerin (Serafinetal.
2019). Further downstream, activation of CMKLR1 by
chemerin leads to phosphorylation of the p44/p42
mitogen-activated protein kinases (MAPK) ERK1/2, p38
MAPK, and Akt in chondrocytes (Berg et al. 2010), he-
patocytes (Feder et al. 2020), human umbilical vein
endothelial cells (HUVEC) (Nakamura et al. 2018), human
granulosa cells (Reverchon et al. 2012), and in fibroblast-
like synovial cells (Kaneko et al. 2011). De Henau et al.
(2016) demonstrated that CMKLR1-mediated ERK1/2
phosphorylation is Gα
i/o
and arrestin 3-dependent.
GPR1
GPR1 or chemerin
2
was identified as a receptor for chemerin
by Barnea et al. (2008). Initially detected in the human
hippocampus, GPR1 mRNA has since been found in murine
ovaries, muscle, and white adipose tissue (Marchese et al.
1994; Rourke et al. 2014; Yang et al. 2016). In the latter,
GPR1 mRNA was detected only in the stromal vascular
Figure 4: According to our previously published model, chemerin-9 (red) binds to CMKLR1 (gray) through distinct aromatic and hydrophobic
sites, adopting a loop conformation.
(A) Overall conformation of chemerin-9 in the CMKLR1 ligand-binding pocket.
(B) F8 binds to a hydrophobic patch in ECL2 consisting of A4.67,L
4.69,F
4.76, and F4.79. (C) F6 interacts with Y2.63 and Y2.68 in TM2 and ECL1,
respectively.
T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine 5
fraction (SVF), but not in adipocytes (Rourke et al. 2014).
Interestingly, while GPR1 expression generally has not
been demonstrated in immune cells, tissue-specific alve-
olar macrophages express GPR1, suggesting that GPR1
expression may be induced when macrophages have
migrated into the lung (Farzan et al. 1997). This could also
be the case for immune cells present in adipose tissue,
explaining the detection of GPR1 in SVF (Rourke et al.
2014). Additionally, expression of GPR1 was also demon-
strated in murine and human skin (Banas et al. 2015).
In a recent study by Rourke et al. (2014), knock-out of
GPR1 in mice had no influence on body weight, fat mass, or
energy expenditure, but led to decreased insulin sensitivity
and exacerbated glucose intolerance in animals fed a high-
fat diet. Unfortunately, no parameters of inflammation
were reported, the role of GPR1 in inflammation remains
unclear.
Chemerin displays a higher affinity to GPR1 than for
CMKLR1, which also translates into higher potency of
chemerin at GPR1 (Barnea et al. 2008; de Henau et al. 2016).
As described for CMKLR1, chemerin-9 is also sufficient to
induce receptor activation at GPR1, and the overall binding
mode of chemerin-9 is shared between these two receptors
(Barnea et al. 2008; Fischer et al. 2021a; de Henau et al.
2016). Several peptides have been proposed as additional
ligands for GPR1 recently: Osteocrin, cholecystokinin,
gastrin-releasing peptide, and the neuropeptide FAM19A1
(Foster et al. 2019; Zheng et al. 2018). Moreover, previous
results from our group showed that GPR1 undergoes
constitutive internalization, enabling receptor-mediated
endocytosis of peptides that are unable to activate GPR1.
These results suggest that GPR1 may not only act as a re-
ceptor for chemerin, but also as a broad-range decoy re-
ceptor for other peptides (Fischer et al. 2021a). However, the
affinity of GPR1 is highest to chemerin (Foster et al. 2019).
GPR1 is an unusual GPCR and it is unclear whether it
may induce G protein signaling. While Barnea et al. (2008)
report weak Ca2+flux in cells transfected with GPR1 and the
promiscuous G protein Gα
15
upon stimulation with 1 µM
chemerin-9, others did not detect any G protein recruitment
to GPR1 (de Henau et al. 2016; Rourke 2015). However,
activated GPR1 rapidly recruits arrestin, followed by sub-
sequent internalization (de Henau et al. 2016). It was sus-
pected that the altered DR3.50Y motif (DHY in GPR1) may be
responsible for the lack of G protein signaling, however,
restoring the canonical DRY motif did not restore G protein
signaling (Rourke 2015). Interestingly, the related C5aR2
shows similar characteristics: This receptor rapidly recruits
arrestin and internalizes in response to stimulation with
C5a, but does not signal through G proteins (Li et al. 2019b).
It is generally assumed that C5aR2 acts as a decoy receptor,
regulating inflammation by scavenging C5a (Scola et al.
2009). A similar role may be conceivable for GPR1, a hy-
pothesis that is supported by recent findings demonstrating
activation-independent, constitutive internalization as an
additional mechanism for GPR1 (Fischer et al. 2021a).
Downstream of arrestin, activation of GPR1 leads to
signaling through the RhoA/ROCK pathway, while no
activation of the MAPK/ERK pathway has been reported
(Rourke et al. 2015). The absence of ERK signaling would
agree with current findings that this pathway cannot be
activated in the absence of active G proteins (Grundmann
et al. 2018). Thus, it is clear that GPR1 does not display
conventional GPCR signaling characteristics, but it re-
mains debated to which extent signaling events triggered
by this receptor play a role in a physiological context. In the
light of recent results, a role for GPR1 as a decoy receptor for
chemerin, and potentially other peptides, seems likely.
CCRL2
CCRL2, the third receptor for chemerin, is expressed on
a wide range of immune cells, i.e., neutrophils, B and T
lymphocytes, macrophages, NK cells, mast cells, and
dendritic cells (Auer et al. 2007; Catusse et al. 2010; Galli-
gan et al. 2004; Hartmann et al. 2008; Migeotte et al. 2002;
Otero et al. 2010; Patel et al. 2001; Zabel et al. 2008). In
most of these cases, CCRL2 expression is upregulated in
response to inflammatory stimuli such as lipopolysaccha-
rides (LPS), interferon (IFN) γ, or TNFα(Schioppa et al.
2020). Expression of CCRL2 has also been demonstrated in
skin (Banas et al. 2015) and a range of endothelial cells,
including inflamed bronchial epithelium (Oostendorp et al.
2004), murine lung endothelial cells, and human primary
endothelial cells (Monnier et al. 2012). Moreover, CCRL2 is
expressed in adipocytes (Muruganandan et al. 2010), he-
patic stellate cells (Zimny et al. 2017), and different tumors
including breast and prostate cancer (Reyes et al. 2017;
Sarmadi et al. 2015).
Consequently, CCRL2 knock-outmice display disturbed
inflammatory responses: However, while Regan-Komito
et al. (2017) report an exaggerated immune response for
CCRL2-deficient mice in a zymosan-induced model of in-
flammation, others demonstrate a protective effect of CCRL2
loss in models of inflammatory arthritis (Del Prete et al.
2017).
Strikingly, no signaling events initiated by CCRL2 have
been detected so far, although it has been confirmed by
several groups that chemerin binds to CCRL2 (de Henau
et al. 2016; Mazzotti et al. 2017; Zabel et al. 2008). Neither
Ca2+mobilization in HEK293 or murine mast cells nor G
6T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine
protein or arrestin recruitment in CHO cells are triggered by
stimulation with chemerin (de Henau et al. 2016). CCRL2
displays slow, constitutive internalization, which is, how-
ever, not altered by the addition of chemerin (Mazzotti et al.
2017). In contrast to the two other chemerin receptors
CMKLR1 and GPR1, CCRL2 does not interact with the
C-terminus of chemerin (de Henau et al. 2016; Zabel et al.
2008). Instead, it is suspected that CCRL2 binds to the
cystatin motif of chemerin through its N-terminus (Zabel
et al. 2008).
An important additional mechanism by which CCRL2
contributes to the orchestration of the immune response is
by heterodimerization with the chemokine receptor CXCR2.
These CCRL2/CXCR2 heterodimers have been shown to
fine-tune neutrophil migration, a concept that is emerging
for an increasing number of chemokine receptors (Del Prete
et al. 2017; Martínez-Muñoz et al. 2018).
Based on these findings, the current understanding is
that CCRL2 contributes to chemerin-mediated chemotaxis
by elevating local concentrations of chemerin, thereby
forming stable membrane-bound chemerin gradients. The
unique interaction of CCRL2 with the cystatin domain of
chemerin suggests that the chemerin C-terminus is free to
activate CMKLR1 when bound to CCRL2, making CCRL2 a
presenting receptor (Schioppa et al. 2020).
The physiological role of chemerin
in healthy individuals
Since the initial discovery of chemerin in 1997, the impor-
tance of this protein to regulate the immune response
has been confirmed by a multitude of different studies
(Ernst and Sinal 2010; Nagpal et al. 1997; Zabel et al. 2006).
As the chemerin receptors are closely related to other
inflammation-regulating GPCR and the closest structural
homolog of chemerin itself is involved in innate immunity,
this may be the most conserved evolutionary role of the
chemerin system.
In the skin, the first barrier against infection, chem-
erin, its receptors, and activating proteases are highly
expressed (Banas et al. 2015; Schultz et al. 2013). Upon
bacterial infection, chemerin can be processed into peptide
fragments with direct antimicrobial activity, offering a first
defense mechanism against infections (Banas et al. 2013).
The same has been demonstrated for the oral cavity, a
major entry point for pathogens (Godlewska et al. 2017). In
the blood stream, inactive prochemerin is constantly
circulating, and is activated upon tissue damage by en-
zymes of the coagulation cascade, or upon inflammation by
neutrophil and mast cell-secreted proteases (Ge et al. 2018;
Zabel et al. 2005). With the help of CCRL2-expressing
endothelial cells and neutrophils, a stable chemotactic
chemerin gradient is formed, attracting CMKLR1-expressing
dendritic cells, NK cells, and macrophages (Parolini et al.
2007; Schioppa et al. 2020; Wittamer et al. 2003). These
leukocytes either directly engage in phagocytosis of the
pathogen (macrophages), or induce apoptosis of virus-
infected or tumorous cells (NK cells). Moreover, as antigen-
presenting cells, dendritic cells and macrophages act by
aiding in the initiation of the adaptive immune response
(Kashem et al. 2017). These results demonstrate that
chemerin plays a critical role in early immunity.
Reproductive functions have emerged as a further field
regulated by chemerin. The two active chemerin receptors
CMKLR1 and GPR1 were both found in the ovary of mice (Li
et al. 2014a). Plasma levels of chemerin undergo significant
changes during normal pregnancy in humans and rats,
where chemerin levels decrease towards the end of preg-
nancy, but are significantly increased in pregnant women
with preeclampsia (Duan et al. 2011; Garces et al. 2012,
2013). Chemerin, CMKLR1, and GPR1 are also expressed in
the testes of male rats, where they may play a role in
regulating steroidogenesis (Li et al. 2014b).
The exact role of chemerin in energy homeostasis is less
clear, with competing evidence pointing in several di-
rections (Helfer and Wu 2018). While it has been confirmed
that chemerin promotes adipogenesis through CMKLR1, the
influence of chemerin signaling on the metabolism seems
context dependent (Ernst et al. 2012; Rouger et al. 2013).
Moreover, chemerin influences insulin signaling, but the
mechanism is still unexplored (Kralisch et al. 2009; Taka-
hashi et al. 2008).
Thus, chemerin is an important regulator of inflamma-
tion, energy homeostasis, and reproductive functions –
complex processes that influence each other. An imbalance
in chemerin activity can, therefore, lead to a wide range of
complicationsasexemplified in Figure 5, which will be
discussed in the following sections.
Chemerin in obesity and related
diseases
During evolution, an excess of nutrients was barely an
issue. These days, however, the modern western lifestyle
has paved the way for a novel epidemic –obesity. The US
center for disease control estimates that around 40% of
adults in the US were obese in 2018, with a clear upward
trend (Hales et al. 2020). In recent years, it has become
T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine 7
increasingly evident that excess body weight and fat mass
have a major influence on a plethora of diseases –ranging
from inflammatory disorders over cardiovascular diseases
to cancer, reproductive dysfunctions, and impeded meta-
bolic functions (Guh et al. 2009). While adipose tissue was
initially seen as mere energy storage, it is now recognized
as an active endocrine organ, expressing a multitude of
signaling molecules; the so called adipocytokines or adi-
pokines (Scheja and Heeren 2019).
Several studies show that chemerin levels of non-
diabetic individuals rise with increasing body mass index
(BMI), a robust correlation that has been independently
confirmed by different groups (Bozaoglu et al. 2007, 2009;
Chang et al. 2016; Sledzinski et al. 2013). Physical exercise
such as high-intensity interval training decreased chem-
erin levels in obese women (Taheri Chadorneshin et al.
2019), and a combined strength and endurance training led
to lower chemerin levels independent of BMI (Stefanov
et al. 2014). Another study showed that bariatric surgery
and a low caloric diet both independently decreased
circulating chemerin levels (Chakaroun et al. 2012),
strengthening the notion that an increased serum con-
centration of chemerin may be a consequence, rather than
a cause, of high-fat mass. More importantly, studies sug-
gest that obesity not only leads to higher total levels of
chemerin but also a higher proportion of bioactive chem-
erin (Chang et al. 2016; Haberl et al. 2018). Excess levels of
chemerin may thus contribute to the chronic low-grade
inflammation associated with obesity and, ultimately, to
the pathogenesis of the many co-morbidities of obesity
(Reilly and Saltiel 2017). Many of these conditions can
occur independently of obesity or each other, but display
complex interactions. The role of chemerin in these dis-
eases will be discussed in the following sections.
Hypertension and atherosclerosis
Obesity, hypertension, and atherosclerosis are tightly con-
nected risk factors for cardiovascular diseases (DeMarco
et al. 2014; Rocha and Libby 2009). Only recently, the role of
chemerin in the development of these complications has
gained the attention of different groups (Ferland and Watts
2015). Current evidence suggests that chemerin contributes
to hypertension by promoting vasoconstriction through
activation of CMKLR1 (Kennedy et al. 2016). This effect has
also been observed in isolated rat aorta, where treatment
with chemerin-9 induced the CMKLR1-dependent contrac-
tion of the isolated rat thoracic aorta, superior mesenteric
artery, and mesenteric resistance artery (Watts et al. 2013).
In line with these results, Kunimoto et al. (2015) demon-
strated that chronic treatment with chemerin increased
blood pressure in mice. Increased chemerin levels are also
an independent risk factor for atherosclerosis in hyperten-
sive patients, and atherosclerotic mice treated with chem-
erin displayed increased lipid accumulation in atheroscle-
rotic plaques (Gu et al. 2015; Jia et al. 2020). Moreover,
van der Vorst et al. (2019) report that apolipoprotein
E-deficient CMKLR1-knockout mice displayed an increasing
proportion of alternatively activated, anti-inflammatory M2
macrophages in atherosclerotic lesions, combined with
attenuated dendritic cell recruitment.
Figure 5: The physiological roles of
chemerin.
In a healthy state, chemerin contributes to
the regulation of a variety of processes
(center). An excess (right) or lack of
chemerin (left) can lead to or promote
several disease states.
8T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine
Diabetes
Perhaps the most prominent co-morbidity of obesity, type 2
diabetes is extremely prevalent among adults, impacting
almost half a billion people in 2019 as estimated in a meta-
study by the international diabetes federation (Saeedi
et al. 2019). Insulin resistance and glucose intolerance
are associated with type 2 diabetes, leading to impaired
glucose uptake and hyperglycemia (Kahn et al. 2006). Pa-
tients with type 2 diabetes display significantly elevated
chemerin expression in adipose tissue compared to healthy
control subjects (Chakaroun et al. 2012). Models of obese
mice display decreased glucose tolerance after chemerin
treatment, suggesting that chemerin may be a driving force
in the pathogenesis of type 2 diabetes (Ernst et al. 2010). On
the other hand, chemerin knockout in mice also leads to
decreased glucose tolerance (Fang et al. 2021). Studies on
the impact of chemerin on glucose uptake by 3T3-L1 adi-
pocytes also come to conflicting results: While Takahashi
et al. (2008) demonstrated increased insulin-dependent
glucose uptake upon stimulation with chemerin, Kralisch
et al. (2009) showed decreased glucose uptake in response
to chemerin treatment. Together, these studies suggest
a complex, context-dependent role for chemerin in the
regulation of glucose uptake.
Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is the most common
cause of infertility among women, and obesity is a major
risk factor for this reproductive disease (Chen et al. 2013;
Gambineri et al. 2002). PCOS refers to a heterogeneous
group of gynecologic disorders that are characterized by
hyperandrogenism (typically excess testosterone), chronic
inflammation, and anovulation (Goudas and Dumesic
1997). Independent of BMI, women with PCOS display
elevated serum chemerin levels compared to healthy in-
dividuals (Abruzzese et al. 2020; Huang et al. 2015; Wang
et al. 2014). Knock-out of CMKLR1 in mice attenuated
dihydrotestosterone-induced clinical signs of PCOS, sug-
gesting a role of chemerin in the pathogenesis of PCOS
(Tang et al. 2016). Lima et al. (2018) suggest that hyper-
androgenism increases chemerin expression in the ovaries,
leading to excess infiltration of inflammatory M1 macro-
phages and, ultimately, granulosa cell apoptosis. This is
supported by earlier findings that chemerin expression is
upregulated in female rats treated with dihydrotestoster-
one, and that chemerin treatment alone was sufficient to
induce follicular growth arrest (Kim et al. 2013). Moreover,
chemerin induced insulin resistance in human granulosa-
lutein cells isolated from PCOS patients, thus potentially
aggravating the abnormalities in ovulation (Li et al. 2019a).
Psoriasis
Psoriasis is an auto-inflammatory skin disease, character-
ized by the formation of thickened plaques on the skin.
Current evidence suggests that obesity predisposes to the
development of this condition and aggravates existing
psoriasis (Jensen and Skov 2016). The pathophysiology of
psoriasis involves early infiltration with macrophages,
dendritic cells, and NK T-cells, leading to the activation of
a T-cell-mediated inflammatory cascade (Armstrong and
Read 2020). Consequently, chemerin expression marks
early psoriatic skin lesions and correlates with dendritic
cell recruitment. In patients with psoriasis, circulating
chemerin levels are elevated, and decrease during treat-
ment with the TNFαantibody infliximab (Lora et al. 2013;
Nakajima et al. 2010). Chemerin and its receptors are
expressed in healthy skin, but pronounced co-localization
of the activating protease KLK7 with chemerin is limited to
psoriatic lesions, suggesting an increased local bioactivity
in psoriatic skin (Banas et al. 2013, 2015; Schultz et al. 2013).
Rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic inflammatory joint
disease, which can cause bone damage, pain, and ulti-
mately, disability (Smolen et al. 2016). Obesity is a risk
factor for developing RA, and arthritis is so frequently
associated with psoriasis that psoriatic arthritis is a distinct
medical diagnosis (Crowson et al. 2013; Veale and Fearon
2018). Chemerin was first identified as the ligand for
CMKLR1 from arthritic synovial fluid, where it is present at
high concentrations (Wittamer et al. 2003). Chemerin and
CMKLR1 are both expressed by chondrocytes, and treat-
ment of these cells with chemerin leads to increased
secretion of inflammatory cytokines (Berg et al. 2010).
Activation of chemerin in synovial fluids was demon-
strated by Zhao et al. (2018), who found elevated levels of
active ChemF156 in synovial fluids of arthritis patients.
Chemerin treatment induced the secretion of IL-6 and CCL2
in fibroblast-like synoviocytes, which may additionally
promote joint inflammation (Kaneko et al. 2011). Interest-
ingly, polymorphonuclear neutrophils, the predominant
cell type recruited to synovial fluid, demonstrate signifi-
cantly upregulated expression of CCRL2 in arthritis, which
T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine 9
could further contribute to chemerin-mediated recruitment
of CMKLR1-expressing leukocytes to the inflamed joint
(Auer et al. 2007).
Nonalcoholic steatohepatitis
Excessive accumulation of fat in the liver, accompanied
by chronic liver inflammation and fibrosis are hallmarks
of nonalcoholic steatohepatitis (NASH), and the risk of
developing NASH is greatly increased in obese patients
(Neuschwander-Tetri 2017). The pathology of NASH in-
volves infiltration of monocytes, neutrophils, and T cells
into the liver and expansion of liver-resident Kupffer and
stellate cells (Nati et al. 2016). Plasma levels of chemerin are
significantly elevated in obese NASH patients compared to
healthy control subjects (Kukla et al. 2010; Sell et al. 2010).
In rodents, NASH correlated with significantly elevated
levels of chemerin in the liver (Krautbauer et al. 2013).
Hepatic expression of chemerin and CMKLR1 mRNA
is increased in NASH, possibly reflecting a chemerin-
mediated accumulation of CMKLR1-expressing leukocytes
(Döcke et al. 2013).
Chemerin in cancer
Over the past years, chemerin has gained increasing in-
terest regarding its role in cancer. Competing roles have
been proposed for chemerin in the context of tumor pro-
gression, either directly by modulating tumor growth and
metastasis through chemerin receptors expressed on tu-
mor cells, or indirectly by recruiting immune effector cells
to the tumor (Shin et al. 2018).
Downregulating local levels of chemerin seems to
contribute to the immune evasion strategy employed by
several cancer types: Chemerin mRNA levels are signifi-
cantly reduced in breast cancer tissues compared to sur-
rounding healthy tissue, and forced overexpression of
chemerin leads to infiltration of dendritic cells, NK cells,
and macrophages into the tumor microenvironment (TME),
thereby suppressing tumor growth (Pachynski et al. 2019).
In melanoma, chemerin-mediated recruitment of NK cells
to the TME suppressed metastasis (Pachynski et al. 2012).
Knockout of CCRL2 was associated with a reduced immune
response to lung cancer in mice, leading to enhanced tumor
growth (DelPrete et al. 2019). This underlines theimportance
of CCRL2 for generating stable chemotactic gradients of
chemerin, which can efficiently recruit CMKLR1-expressing
leukocytes to sites of inflammation In hepatocellular carci-
noma, decreased local expression of chemerin was
associated with poor patient prognosis, and administration
or forced overexpression of chemerin in mice reduced he-
patocellular carcinoma metastasis (Haberl et al. 2019; Li
et al. 2018). Low expression levels of chemerin also correlate
with decreased patient survival in prostate cancer and sar-
coma, where chemerin induces the expression of PTEN, a
critical tumor suppressor gene (Rennier et al. 2020). Conse-
quently, forced overexpression of chemerin in the prostate
cancer cell line DU145 inhibited tumor growth in vivo and
increased T cell-mediated cytotoxicity (Rennier et al. 2020).
Thus, downregulating chemerin expression seems a
widespread strategy among cancers to evade innate immu-
nity, especially NK cells –the first responders of the immune
system to emerging tumors (Guillerey et al. 2016). However,
tumor-expressed CMKLR1 seems to be directly involved in
the progression of some cancers: High CMKLR1 expression
by neuroblastoma cells correlates with decreased patient
survival, and blocking CMKLR1 reduced viability of these
cells in vitro and tumor progression in vivo (Tümmler et al.
2017). Colorectal cancer tissue expresses increased levels
of CMKLR1, correlating with tumor size and angiogenic
markers, suggesting that chemerin may promote angiogen-
esis during tumor growth (Kiczmer et al. 2020). Moreover,
chemerin promotes the invasion of oesophageal squamous
cancer cells in vitro through CMKLR1 (Kumar et al. 2016).
The chemerin system as a
therapeutic target –state of the art
GPCR constitute the largest family of membrane proteins,
and current estimates suggest that around 35% of ap-
proved drugs target GPCR (Sriram and Insel 2018). Thus, the
chemerin receptors, mediating chemerin bioactivity in a
wide range of diseases, are attractive for therapeutic inter-
vention as well. As the majority of evidence suggest CMKLR1
as the receptor responsible for mediating the inflammatory
properties of chemerin, most studies have focused on this
receptor for drug development.
Two compounds targeting CMKLR1 have been tested in
clinical trials to date: CCX832, a CMKLR1 antagonist by
ChemoCentryx and GlaxoSmithKline was tested in phase I
clinical trials in 2011, but was discontinued (Chemocentryx
2011). Although its structure remains undisclosed, it is
frequently used as a tool compound to study CMKLR1
pharmacology (Kennedy and Davenport 2018). In diabetic
ob/ob mice, CCX832 decreased body weight, insulin and
glucose levels, and oxidative stress, suggesting that
blocking CMKLR1 activation could be beneficial for treating
type 2 diabetes (Neves et al. 2018). A phase II clinical study
10 T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine
of the resolvin E1 analog RX-10045 in 2019 concluded
insufficient efficacy in the treatment of ocular inflamma-
tion (Sablinski 2019). However, although Hauser et al.
(2017) report CMKLR1 as the target of RX-10045, this pairing
was not experimentally confirmed.
Graham et al. (2014) identified 2-(α-naphtoyl) ethyl-
trimetyhlammonium iodide (α-NETA) as an inhibitor of
chemerin-induced recruitment of arrestin 3 to CMKLR1.
This compound was effective in suppressing experimental
autoimmune encephalomyelitis, a murine model of mul-
tiple sclerosis (MS) (Graham et al. 2014). Later, more potent
derivatives of this molecule were identified in structure-
activity relation studies, which proved superior to the
FDA-approved MS drug Tecfidera in the same model sys-
tem (Kumar et al. 2019). Moreover, treatment with α-NETA
reduced clonogenicity and cell viability of neuroblastoma
cells in vitro and tumor growth in vitro (Tümmler et al.
2017). However, no binding data are reported for this
compound, and the mechanism of action (orthosteric or
allosteric) at the CMKLR1 remains unclear.
Imaizumi et al. (2019) engaged in extensive SAR
studies of 2-aminobenzoxazol analogs as inhibitors of
CMKLR1-mediated Ca2+flux and migration of the dendritic
cell line CAL-1. These analogs display high oral bioavail-
ability and good pharmacokinetics in monkeys (Imaizumi
et al. 2020). However, the authors state that these com-
pounds inhibit CMKLR1-mediated Ca2+flux by inducing
CMKLR1 internalization (Imaizumi et al. 2019, 2020). This is
in contrast to the mode of action of other known modula-
tors of GPCR signaling, asking for a more detailed phar-
macological investigation of these compounds (Burkert
et al. 2017; Konieczny et al. 2020; Yang et al. 2018). An
overview of small molecule compounds targeting CMKLR1
is given in Figure 6.
Chemerin-derived peptides have also been investi-
gated regarding their therapeutic potential for various
diseases: Cash and coworkers reported that the C-terminal
chemerin fragment C15, terminating at A155, suppressed
inflammation and promoted wound healing through
CMKLR1 (Cash et al. 2008, 2014). However, C15 lacks the
C-terminal F156, which is critical for binding to CMKLR1,
and others have not confirmedanyactivityofC15at
CMKLR1 (Fischer et al. 2021c; Luangsay et al. 2009; Wit-
tamer et al. 2003, 2004; Yamaguchi et al. 2011). Thus, it
remains unclear how C15 mediates its beneficial effects.
Using a murine model of pancreatic diabetes mellitus, Tu
et al. (2020) demonstrated that treatment with chemerin-9
significantly alleviated glucose intolerance and insulin resis-
tance through increased expression of the glucose transporter
GLUT2. However, the plasma half-life of chemerin-9 is less
than 10 min, suggesting that stabilized variants would be
even more beneficial (Bandholtz et al. 2012; Shimamura
etal.2009).Suchstabilized,68Ga-labeled derivatives have
demonstrated high potential as PET tracers in murine breast
cancer xenograft models and may develop into future thera-
peutics (Erdmann et al. 2019). The same principle has been
applied by using metabolically stable, cyclic analogs of
the chemerin C-terminus, which can efficiently shuttle toxic
payloads into CMKLR1-expressing cells (Fischer et al. 2021b).
Such methotrexate-coupled cyclic chemerin derivatives
demonstrated superior toxicity than free methotrexate on
CMKLR1-expressing cells, while no toxic effect was observed
in cells lacking the receptor. Thus, peptide-drug conjugates
based on cyclic chemerin-9 analogs may be promising for
targeted cancer therapies.
In conclusion, therapeutics targeting the chemerin
system have focused on CMKLR1 so far. Their potential
indications are as diverse as the morbidities that chemerin
Figure 6: Structures of selected small molecule compounds targeting CMKLR1.
The Resolvin E1 analog RX-10045 (left) was tested in phase II clinical trials for the treatment of ocular inflammation. The antagonist α-NETA
(center) is described as a sub-micromolar inhibitor of chemerin-induced arrestin 3 recruitment to CMKLR1 and is widely used in experimental
studies. The recently developed 2-aminobenzoxazol analog 2(right) demonstrated promising potency and pharmacokinetics, but its mode of
action remains to be clarified.
T.F. Fischer and A.G. Beck-Sickinger: Chemerin –exploring a versatile adipokine 11
is involved in, but no drugs targeting the chemerin system
have been approved to date. This may be, in part, due to the
lack of information on the molecular interactions govern-
ing the bioactivity of chemerin, which are still not suffi-
ciently understood.
Conclusions
Chemerin is an adipokine involved in adipose tissue ho-
meostasis, immunity, and the regulation of reproductive
functions. A wide range of inflammatory and obesity-
related diseases is driven by an excess of active chemerin,
while downregulation of chemerin expression helps several
cancer types to avoid recognition by the innate immune
system. Multiple studies have allowed a glimpse at the
therapeutic potential that lies in addressing the chemerin
system, but so far, no compounds have successfully
exploited this potential to become approved drugs.
The regulation of chemerin activity takes place on the
levels of expression, proteolytic activation and deactiva-
tion, as well as receptor binding. With three chemerin re-
ceptors displaying distinct signaling properties, the latter is
particularly complex. CMKLR1 is the most intensely studied
receptor for chemerin, and seems to mediate most of its
functions. Recruiting NK cells, macrophages, and dendritic
cells to sites of inflammation, the pro-inflammatory role of
chemerin-induced CMKLR1 activation is firmly established
in most contexts. Controversy exists concerning the role of
GPR1, the second chemerin receptor. Displaying uncon-
ventional signaling properties, i.e., reduced or absent G
protein signaling, it is unclear whether this receptor exerts
distinct chemerin-mediated functions, or if it predomi-
nantly acts as a decoy receptor. CCRL2, the third chemerin
receptor, is essential to build up stable chemotactic
chemerin gradients, and no CCRL2-mediated chemerin
signaling has been described to date.
Successful therapeutic interventions targeting the
chemerin system will rely on improved understanding of
the molecular mechanisms governing the bioactivity of this
adipokine.
Author contributions: All the authors have accepted
responsibility for the entire content of this submitted
manuscript and approved submission.
Research funding: This study was financially supported
by the Deutsche Forschungsgemeinschaft (DFG), German
Research Foundation, project number 209933838 –
SFB1052 –Z05.
Conflict of interest statement: The authors declare no
competing financial interests.
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