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Proinflammatory S100 proteins in arthritis and autoimmune disease.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 12, December 2004, pp 3762–3771
DOI 10.1002/art.20631
© 2004, American College of Rheumatology
REVIEW
Proinflammatory S100 Proteins in
Arthritis and Autoimmune Disease
Dirk Foell and Johannes Roth
range of pro- and antiinflammatory activities. This heterogeneity is important for propagation or down-regulation
of the initiated inflammatory process and the resulting
tissue damage (3).
Pro- and antiinflammatory properties of macrophages are mainly dependent on the stage of differentiation, as well as on distinct mechanisms of activation.
One important signaling mechanism regulating these
processes in phagocytes is the elevation of free intracellular calcium concentrations. Calcium ions induce conformational changes of calcium-binding proteins which
allow their interaction with specific intracellular target
structures. The major calcium-binding proteins, which
are specifically expressed in granulocytes and early
differentiation stages of monocytes, are S100A8,
S100A9, and S100A12. In this review, we bridge the
current understanding of the biologic functions assigned
to these proinflammatory S100 proteins with a prospect
for potential diagnostic and therapeutic strategies for
arthritis and autoimmune disorders.
Introduction
Aberrant adaptive immune responses and disturbed activation of innate immune mechanisms are
involved in the pathogenesis of arthritis and other
autoinflammatory diseases (1). The innate immune system is equipped with a large repertoire of cellular and
humoral components which are normally capable of
establishing rapid effector mechanisms that protect the
host organism from various challenges. The parallel
engagement of different signaling pathways and the
extensive interconnection between many proinflammatory mediators lead to a redundancy and selfamplification of innate immune responses. Disturbed
regulation of this complicated network involving proand antiinflammatory factors may cause autoinflammation (2).
An important cell population integrating many of
these mechanisms is the population of phagocytes, especially macrophages (3), due to a virtually endless
source of soluble mediators and cell surface receptors.
Neutrophilic granulocytes and macrophages are abundant in the inflamed synovial membrane, and their
activation correlates significantly with the severity of
inflammatory arthritis. Macrophages may be involved in
the initiation of arthritis as antigen-presenting cells, but
they also contribute to disease progression since they
exhibit widespread proinflammatory, destructive, and
remodeling capabilities (4,5). However, macrophages
are not a homogeneous cell population, since they
encompass distinct phenotypes which exhibit a wide
The S100 family of calcium-binding proteins
Among the several groups of calcium-binding
proteins, the family of S100 proteins comprises the
largest group. Three phagocyte-specific S100 proteins
comprise the group of calgranulins. The members of this
protein family, S100A8, S100A9, and S100A12, are
characterized by a unique expression pattern, with
strong prevalence in cells of myeloid origin.
S100A8 and S100A9. S100A8 and S100A9 represent the majority of the calcium-binding capacity in
phagocytes (6,7). In neutrophilic granulocytes, S100A8
and S100A9 represent ⬃40% of the soluble cytosolic
protein content (7). The human S100A8 protein (also
known as myeloid-related protein 8 [MRP-8], calgranulin A, or L1 light chain) is made up of 93 amino acids
and has a molecular weight of 10.8 kd. The human
S100A9 protein (MRP-14, calgranulin B, and L1 heavy
Supported by a grant from the Interdisciplinary Center for
Clinical Research (Fo2/26/04) of the University of Muenster.
Dirk Foell, MD, Johannes Roth, MD: University of Muenster, Muenster, Germany.
Address correspondence and reprint requests to Johannes
Roth, MD, Institute of Experimental Dermatology, University of
Muenster, Roentgenstrasse 21, D-48149 Muenster, Germany. E-mail:
rothj@uni-muenster.de.
Submitted for publication April 14, 2004; accepted in revised
form August 16, 2004.
3762
S100 PROTEINS IN ARTHRITIS AND AUTOIMMUNITY
chain) consists of 114 amino acids with a molecular
weight of 13.2 kd (8,9). The amino acid sequence of
S100A9 reveals highest homology with the other
phagocyte-specific proteins S100A8 (30%) and S100A12
(46%).
The genes for both proteins are found in a cluster
on human chromosome 1q21. The gene structure is
typical for members of the S100 family, characterized by
a pattern of 3 exons separated by 2 introns. The expression of S100A8 and S100A9 is highly tissue specific. Both
proteins are present in circulating granulocytes and
monocytes, but neither in resting tissue macrophages
nor in lymphocytes (10,11). In general, S100A8 and
S100A9 show a parallel regulation of gene expression,
but differential expression of S100A8 and S100A9 has
been found to indicate a chronic type of inflammation,
e.g., in granulomatous lung diseases, some forms of
glomerulonephritis, and chronic renal allograft rejection
(12–14). Expression of these S100 proteins in monocytes
and macrophages is restricted to early differentiation
stages and declines rapidly during maturation (11,15).
Different inflammatory stimuli suppress transcription of
S100A8 and S100A9 messenger RNA restricting the
expression of these proteins to early stages of inflammatory processes. Expression in some epithelial cells, e.g.,
keratinocytes under inflammatory conditions or mucous
epithelium of the esophagus, is the single exception to
this myeloid expression pattern (16,17).
Most of the S100 proteins exist in homodimers,
but some also assemble to heterodimers. The preferred
form for human S100A8 and S100A9 is the S100A8/
S100A9 heterodimer. This complex was also called
leukocyte protein L1 or cystic fibrosis antigen, and is still
designated as calprotectin by some research groups (18).
Trimer formation of S100A8 and S100A9 has been
suggested from studies using gel chromatography, but is
contradicted by structural data obtained by nuclear
magnetic resonance analysis (19,20). Homodimerization, as well as dimerization with other S100 proteins,
especially with S100A12, has been excluded for human
S100A8 and S100A9 (21,22). The S100A8/S100A9 heterodimers associate with (S100A8/S100A9)2 heterotetramers in a calcium-dependent manner (20). Calcium
binding results in an exposure of hydrophobic domains
to the surface of the protein complex, which may alleviate interaction with target proteins (19,23).
Elevation of intracellular calcium concentrations
induces interactions of S100A8/S100A9 complexes,
which are mainly localized in the cytosol of resting
phagocytes, with membrane and cytoskeletal structures
indicating a role in cytoskeletal rearrangement and cell
3763
migration after activation of phagocytes (6,11,24). In this
context, S100A9 acts as a regulatory subunit in the
S100A8/S100A9 complex and integrates inputs from 2
major signaling pathways: the p38 microtubuleassociated protein kinase cascade, and calciumdependent signal transduction (6). Accordingly, targeted
deletion of the S100A9 gene induces changes in the
migratory properties of murine phagocytes. Stimulation
of S100A9-deficient neutrophils with interleukin-8
(IL-8) failed to provoke an up-regulation of CD11b and
to stimulate migration upon a chemotactic gradient (24).
Deletion of the S100A8 gene is not compatible with life,
which confirms the biologic relevance of the S100A8/
S100A9 complex (25).
S100A12. More recently, S100A12 has been described as an additional phagocyte-specific S100 protein
(26,27). Calgranulin C, calcium-binding protein in amniotic fluid 1, and extracellular newly identified receptor
for advanced glycation end product–binding protein
(EN-RAGE) are synonyms of S100A12. The primary
structure of human S100A12 consists of 91 amino acids
with a molecular mass of 10.4 kd. Human S100A12
shows highest homologies with S100A9 (46%) and to
S100A8 (40%). The human S100A12 gene, localized
within the S100 gene cluster on chromosome 1q21
between the S100A8 and S100A9 genes, is composed of
3 exons which are divided by 2 introns. Unlike proteins
S100A8 and S100A9, homologs with protein S100A12
have only been identified in some species. There is
evidence that chromosomal rearrangements during rodent evolution damaged the murine S100A12 gene, indicating the absence of the protein in mice (28).
The occurrence of human S100A12 in the cytoplasm of granulocytes resembles the distribution pattern
of S100A8/S100A9, with the difference being that it is
less abundant (29,30). In the presence of calcium,
S100A12 forms homodimers, but there is no complex
formation with S100A8 or S100A9 (22). Thus, S100A12
acts individually during calcium-dependent signaling,
independent of S100A8/S100A9 (22).
Extracellular functions of phagocyte-specific S100
proteins
Release by activated phagocytes. Since S100 proteins lack the leader sequence typical for intracellular
transport via the endoplasmic reticulum and Golgi complex (mechanisms by which they pass the plasma membrane), an alternative secretory pathway is implied. It
has been demonstrated that S100A8, S100A9, and
S100A12 are released by stimulated phagocytes (31–33).
3764
Figure 1. Secretion of S100A8/S100A9 (A8 and A9). Activation of
protein kinase C (PKC) through stimulation with lipopolysaccharide
(LPS), interleukin-1␤ (IL-1␤), tumor necrosis factor (TNF), or other
activators causes secretion of S100A8/S100A9. However, additional
calcium signals following contact with stimulated endothelium or
extracellular matrix proteins are necessary to induce secretion of
S100A8/S100A9. Active secretion of the heterodimer by human monocytes and activated granulocytes uses an alternative pathway, which
bypasses the Golgi route and depends on intact microtubules (MT).
However, the mechanism of crossing the lipid bilayer of the plasma
membrane is completely unknown. Released S100A8/S100A9 interacts
with surface receptors on target cells, thereby inducing cellular responses through as-yet-unknown signaling pathways. However, reported effects include up-regulation of adhesion molecules on leukocytes (CD11b) and induction of apoptosis. RAGE ⫽ receptor for
advanced glycation end products.
Secretion of the S100A8/S100A9 heterodimer by human
monocytes is an energy-dependent process which requires intact microtubules (32). Both activation of protein kinase C and additional calcium signals through
contact with stimulated endothelium are necessary to
induce secretion. In contrast, contact of monocytes with
resting endothelium was found to inhibit protein kinase
C–induced secretion (34). These data confirm specific
release of S100A8/S100A9 during the interaction of
phagocytes with activated endothelium (Figure 1). The
exact mechanisms of S100A12 secretion remain to be
defined, but published observations indicate a similar
release by granulocytes which adhere to endothelium at
sites of local inflammation (33,35).
Effects on endothelium. Since secretion of
phagocyte-specific S100 proteins is associated with adherence and transendothelial migration, cells within the
endothelial layer are among the first cells targeted by
released S100A8/S100A9 or S100A12. S100A12 has
been implicated in a novel inflammatory axis involving
RAGE, a multiligand receptor of the immunoglobulin
FOELL AND ROTH
superfamily expressed on endothelium and cells of the
immune system (36,37). S100A12 binds to RAGE;
whether this is the case for S100A8 and S100A9 has not
been established. The binding of S100A12 and possibly
S100A8/S100A9 to RAGE or other surface receptors
results in activation of various intracellular signaling
pathways. As a consequence, surface expression of vascular cell adhesion molecule 1 (VCAM-1) increases on
endothelial cells after S100A12 stimulation. Enhanced
binding of integrin very late activation antigen 4–bearing
mononuclear cells to S100A12-stimulated endothelium
has been demonstrated (36). In addition, S100A12 increased expression of intercellular adhesion molecule 1
(ICAM-1), thereby providing a mechanism by which
polymorphonuclear leukocytes might be attracted to
S100A12-stimulated endothelium as well (36). Induction
of VCAM-1 and ICAM-1 expression by S100A12 is, at
least in part, mediated by activation of NF-␬B (38).
Other cell surface molecules have been described
that could act independently from RAGE or as coreceptors to enhance the affinity of RAGE for S100A12,
S100A8, and S100A9. The S100A8/S100A9 complex
binds to endothelial cells via the S100A9 molecule by
specific interaction with heparan sulfate proteoglycans
(39). In addition, both molecules modulate transendothelial migration of leukocytes by binding of novel
carboxylated glycans which are expressed by inflammatory activated endothelial cells (40). However, the exact
effects of S100A8/S100A9 on endothelium remain to be
described in greater detail. In contrast to human
S100A8, direct chemotactic potency of the murine counterpart may contribute to transendothelial migration in
mice (41). The different function of S100A8 with obvious chemotactic properties in mice compared with humans may be due to substitution of lacking murine
S100A12 by S100A8 in mice. The release of S100A8/
S100A9 and/or S100A12 at sites of inflammation observed in vivo is feasible to constitute a positive feedback
loop in which interaction of primed phagocytes with
endothelial cells facilitates the further recruitment of
even more leukocytes (32,42–44).
Activation of immune cells. The complex of
S100A8/S100A9 increases binding activity of the integrin
receptor CD11b/CD18 on neutrophils, which enhances
adhesion of these cells to endothelial cells and extracellular matrix proteins (44). S100A12 exhibits direct chemotactic effects on phagocytes (42). Furthermore, activation of RAGE by S100A12 up-regulates expression of
proinflammatory cytokines, such as tumor necrosis factor (TNF) and IL-1␤, by murine macrophage-like BV-2
cells (36). Peripheral blood mononuclear cells (PBMCs)
S100 PROTEINS IN ARTHRITIS AND AUTOIMMUNITY
3765
lished observations). Antimicrobial properties of
S100A8, S100A9, and S100A12 provide further evidence
that these proteins contribute to unspecific host defense
mechanisms (18). Deleterious effects on fibroblasts and
on the recovery of inflammatory tissue from S100A8/
S100A9 have been demonstrated (45,46). Thus, S100A8/
S100A9 released at sites of inflammation may directly
contribute to tissue damage mediated by macrophages
probably along with other factors, e.g., oxidative stress.
RAGE-independent pathways may be responsible for
the induction of apoptosis by S100 proteins (47). Due to
zinc-binding properties of S100A8/S100A9, zinc depletion has been discussed as a mechanism underlying
proapoptotic effects of these proteins (48).
The role of S100 proteins in synovial inflammation
Figure 2. Proinflammatory effects of S100A12 (A12) on target cells.
S100A12 secretion by granulocytes stimulated with TNF or LPS has
been demonstrated. The binding of S100A12 to RAGE or to other
surface receptors results in activation of various intracellular signaling
pathways. NF-␬B–driven up-regulation of adhesion molecule surface
expression on endothelial cells has been demonstrated for vascular cell
adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1
(ICAM-1). Activation of RAGE by S100A12 also results in upregulated expression of proinflammatory cytokines, such as TNF and
IL-1␤, by other phagocytes. Released TNF may stimulate granulocytes
to secrete S100A12, thereby establishing a self-amplifying positive
feedback loop. S100A12-activated peripheral blood mononuclear cells
release IL-2 and show enhanced expression of cytokines. See Figure 1
for other definitions.
exposed to S100A12 displayed enhanced release of IL-2
into culture supernatants. In addition to these findings,
an enhanced mitogenic response to crosslinking CD3/
CD28 after stimulation of PBMCs with S100A12 was
noted (36). Taken together, the results of these in vitro
studies demonstrated that released S100 proteins activate immune cells critical to pathogenesis of inflammation by triggering proliferation and generation of cytokines (Figure 2).
Cytotoxic effects. It has been suggested that
S100A8 and S100A9 exert regulatory activities in inflammatory processes through effects on the survival or
growth of cells participating in the inflammatory reaction and tissue homeostasis. The complex of S100A8/
S100A9 exhibits proapoptotic effects on fibroblasts,
myocytes, and lymphocytes in vitro, but not on neutrophils or monocytes (ref. 45 and Foell D, et al: unpub-
A direct role of S100A8 and S100A9 in inflammatory processes has been confirmed by identification
of a new inflammatory syndrome characterized by extraordinarily high expression of these two calciumbinding molecules (49). Arthritis is a symptom in most
affected patients, and there is accumulating evidence for
a role of proinflammatory S100 proteins in the pathogenesis of synovial inflammation and autoimmune diseases (Tables 1 and 2).
Experimental models of arthritis. Data from
experimental models of arthritis indicate a direct role of
phagocyte-specific S100 proteins in synovitis. Use of a
DNA subtraction technique for identification of
arthritis-specific genes led to the identification of
S100A8 and S100A9 in rats. Expression correlated with
chronic inflammation in arthritis-susceptible LEW/n
rats, but was absent in F344/n rats, which do not develop
arthritis in response to streptococcal cell wall
peptidoglycan–polysaccharide complexes (50). There is
one contradictory report showing a slight attenuating
effect of S100A8/S100A9 on avridine-induced arthritis in
rats which, however, was not statistically significant (51).
Experimental data obtained from mice lacking
the proinflammatory Fc␥ receptor I (Fc␥RI) and
Fc␥RIII, or the antiinflammatory Fc␥RII, show a clear
correlation of disease activity with expression of S100A8
and S100A9 in complex-mediated as well as antigeninduced arthritis (52,53). Interestingly, this effect was
not simply due to quantitative differences of infiltration,
but rather reflected the state of activation of synovial
macrophages (52–54). There was also an accumulation
of S100A8- and S100A9-expressing macrophages in
close proximity to the cartilage surface, and a clear
correlation of S100A8 and S100A9 expression with signs
3766
FOELL AND ROTH
Table 1.
Disease associations of S100A8/S100A9
Condition
Species
Ref.
Immune complex–mediated arthritis
Antigen-induced arthritis
Immune complex–induced arthritis
Avridine-induced arthritis
Rheumatoid arthritis
Psoriatic arthritis
Reactive arthritis
Juvenile idiopathic arthritis
Inflammatory bowel disease
Systemic lupus erythematosus/glomerulonephritis
Systemic sclerosis
Dermatomyositis/polymyositis
Hyperzincemia/systemic inflammation
Mouse
Mouse
Rat
Rat
Human
Human
Human
Human
Human
Human
Human
Human
Human
52, 53
54
50
51
9, 10, 58, 60–62, 80
60
62
34, 67–70
55, 75
13, 14, 71
77
46
49
of cartilage destruction as shown by matrix
metalloproteinase–mediated proteoglycan damage,
chondrocyte death, and development of erosions (52–
54). These data indicate a direct role of S100A8 and
S100A9 in the destructive process of inflammatory arthritis (Figures 3A–D), which is supported by the finding
that these markers are associated with production of
IL-1 and oxidative radicals in inflamed tissues (55,56). In
addition, these experiments demonstrate that expression
of S100A8 and S100A9 in vivo is somehow regulated by
the expression of pro- and antiinflammatory Fc␥R on
phagocytes. Analysis of the course of experimental arthritis in S100A9⫺/⫺ mice is the subject of current
investigations.
S100A12 has also been demonstrated to trigger
synovial inflammation in mice with collagen-induced
arthritis (57). The reported proinflammatory effects
involving cytokine production and metalloproteinase
activation within the synovium depend on interaction of
S100A12 with RAGE (36,37).
Rheumatoid arthritis. S100A8 and S100A9 have
been initially identified in the context of rheumatoid
arthritis (RA). Activated phagocytes expressing these
S100 proteins are among the first cells infiltrating inTable 2. Disease associations of S100A12
Condition
Species
Ref.
Collagen-induced arthritis
Colitis
Hypersensitivity
Vasculitis
Rheumatoid arthritis
Psoriatic arthritis
Juvenile idiopathic arthritis
Vasculitis
Inflammatory bowel disease
Mouse
Mouse
Mouse
Mouse
Human
Human
Human
Human
Human
37, 57
36
36
65
30, 35, 57, 63
35
66
73
33
flammatory lesions in the synovium (9,10). Early recruited phagocytes expressing S100A8 and S100A9 have
been found in the sublining layer of inflamed synovial
tissue (58). In patients with active arthritis, S100A8/
S100A9 is also expressed in macrophage-like cells within
the lining layer, which show altered activation and
differentiation under inflammatory conditions (Figure
3E). The expression of S100A8 and S100A9 was found
to be strongest at the cartilage–pannus junction, which is
the prime site of cartilage destruction and bone erosion
in arthritis (58). Direct effects of S100A8/S100A9 on
cartilage cells still remain to be analyzed, but there is
evidence for release of S100A8/S100A9 in synovial fluid
obtained from inflamed joints (34,59,60). S100A8/
S100A9 concentrations in synovial fluid are ⬃10-fold
higher than concentrations in serum obtained in parallel
from individual patients (34,60). Elevated S100A8/
S100A9 serum concentrations therefore reflect release
of these proteins from activated phagocytes within the
synovium and the synovial fluid.
There are 3 major consequences of this synovial
expression pattern and the in vitro data presented above:
1) S100A8/S100A9 expression is associated with inflammation in the synovial tissue; 2) S100A8/S100A9 at the
site of inflammation activates endothelium and thereby
facilitates further recruitment of inflammatory cells into
the synovial tissue; and 3) the resulting increase of
S100A8/S100A9 serum concentrations may be an important serum marker of the extent of local inflammation in
the affected joints.
In clinical practice, laboratory parameters most
frequently used in the monitoring of disease activity in
chronic arthritis are C-reactive protein level and erythrocyte sedimentation rate, although sensitivity and specificity for changes in synovial inflammation are limited.
S100 PROTEINS IN ARTHRITIS AND AUTOIMMUNITY
Figure 3. Expression of S100A9 at sites of inflammation. A and B, In an
experimental model of immune complex–mediated arthritis in mice,
S100A9 was extensively expressed in inflamed synovial tissue (solid
arrow), especially at the cartilage–pannus junction (open arrow). C and D,
In mice treated with an interleukin-1 receptor antagonist, decreased local
expression of S100A9 correlated well with reduced arthritis (arrows mark
sites corresponding to the arrows in A and B). E, In inflamed synovial
tissue obtained from a patient with rheumatoid arthritis (RA), S100A9
expression was found in the lining layer (solid arrow) as well as in
infiltrating cells in the sublining (open arrow). F, In contrast to RA,
S100A9 expression was more pronounced in the perivascular tissue of
inflamed synovium (solid arrows) in a patient with psoriatic arthritis. G,
S100A9 expression by infiltrating macrophages (solid arrow) showed a
clear association with muscle fiber necrosis (indicated by the central
localization of nuclei in degenerating fibers) (open arrows) in a biopsy
specimen from inflamed muscle in a patient with dermatomyositis. H, In
a patient with glomerulonephritis accompanying systemic lupus erythematosus, the majority of infiltrating macrophages expressed S100A9 in
affected glomeruli. In all stainings, S100A8 colocalized with S100A9 and
showed an identical expression pattern (not shown). (Original magnification ⫻ 100 in A and C; ⫻ 200 in B and D; ⫻ 400 in E–H.)
3767
Numerous studies on serum levels of S100A8/S100A9 in
patients with RA have confirmed the excellent correlation of serum S100A8/S100A9 concentrations with the
inflammatory activity of arthritis (60–62). The diagnostic capacity of S100A8/S100A9 as a marker of synovial
inflammation is superior to that of C-reactive protein or
erythrocyte sedimentation rate (60–62).
More recently, the proinflammatory role of
S100A12 in synovitis has been emphasized. S100A12
levels have been found to be increased in the synovial
fluid and serum of patients with RA but undetectable in
patients with osteoarthritis (63). S100A12 is strongly
expressed in inflamed synovial tissue, whereas it is nearly
undetectable in synovia of control subjects or patients
after successful treatment (35). Inflamed synovium was
found to contain S100A12-positive neutrophils in the
sublining and interstitial regions, often surrounding the
perivascular tissue, but to a lesser extent in the synovial
lining layer (30). Serum levels of S100A12 correlate well
with disease activity (35). Indirect evidence indicated
involvement of S100A12 binding to RAGE in the context of synovial inflammation. A RAGE variant with a
glycine–serine substitution at amino acid position 82
within the ligand binding domain of this receptor is
associated with an amplified inflammatory response
upon engagement by S100A12. Individuals with the
genetic variant of the RAGE G82S polymorphism exhibited increased susceptibility for the development of
arthritis (57). Thus, exaggerated signaling by different
receptor variants in response to S100A12 ligation may
contribute to enhanced proinflammatory mechanisms in
synovitis.
Psoriatic arthritis. Psoriatic arthritis (PsA) is not
as destructive as RA, possibly due to a lower degree of
synovial macrophage infiltration. Nevertheless, freshly
recruited phagocytes contribute to synovial inflammation in PsA. The expression pattern of S100A8 and
S100A9 in PsA is clearly distinct from that in RA, as
these molecules are predominantly found in perivascular
areas of the synovial sublining layer (Figure 3F). This
expression is significantly reduced in serum and synovium from patients with PsA after successful methotrexate treatment (60). Similar results have been obtained
with S100A12 (35). The perivascular distribution of S100
proteins is particularly intriguing, since angiogenesis and
altered function of microvascular endothelium have
been reported to be an important mechanism of synovial
inflammation in PsA (64). Activation of endothelial cells
is a key property of S100A12, and the enhanced angiogenesis in models of diabetic mice was found to be
3768
inhibited by blocking the interaction of S100A12 with
RAGE (65).
Juvenile idiopathic arthritis. S100A8, S100A9,
and S100A12 have also been detected in serum and
synovial fluid of patients with juvenile idiopathic arthritis (JIA) (34,66). Serum concentrations of S100A8/
S100A9 correlated well with individual disease activity in
long-term studies of children with JIA (34,66–68). Findings of preliminary studies suggested that patients with
clinically inactive JIA but elevated levels of S100A8/
S100A9 or S100A12 may be at risk for disease flares
(66,69).
Children with systemic-onset JIA, characterized
by massive neutrophil activation, have serum concentrations of phagocyte-specific S100 proteins up to 20-fold
higher than those found in patients with sepsis or other
inflammatory disorders (66,68,70). Therefore, S100A8/
S100A9 and S100A12 may be useful to distinguish
systemic-onset JIA from systemic infections, which represent the most important differential diagnosis. Interestingly, patients with systemic onset of JIA also show
extensive expression of S100A8/S100A9 in the dermal
epithelium, indicating for the first time an active role of
this cell type during the initiation of a systemic autoimmune disorder (68).
S100 proteins in other autoimmune disorders
Dermatomyositis. In dermatomyositis, polymyositis, and inclusion body myositis there is a clear association of S100A8 and S100A9 expression by infiltrating
macrophages with degeneration of myofibers (Figure
3G). S100A8 and S100A9 inhibited proliferation and
differentiation of myoblasts in vitro and induced apoptosis of these cells via activation of caspase 3, indicating
that activated macrophages promote destruction and
impair regeneration of myocytes in the course of inflammatory myopathies via release of these S100 proteins.
Systemic lupus erythematosus. In a crosssectional study of 100 patients with systemic lupus
erythematosus (SLE), elevated serum concentrations of
S100A8/S100A9 were detected, which correlated significantly with the SLE Disease Activity Index (71). Immunohistochemical analysis of renal biopsy samples demonstrates that expression of S100A8/S100A9 by
infiltrating macrophages in the glomeruli of patients
with SLE corresponds to the severity of the inflammatory process (Figure 3H). Macrophages in the renal
interstitium expressed S100A8 and S100A9 without concomitant formation of their heterodimer, indicating a
FOELL AND ROTH
chronic type of inflammatory reaction in the interstitium
in SLE glomerulonephritis (13).
Vasculitis. Enhanced expression of S100 proteins
in diabetic apolipoprotein E⫺/⫺ mice with vascular inflammation has been reported (72). Elevated serum
concentrations of S100A12 have been detected in Kawasaki disease, which correlated with the inflammatory
disease activity in this acute vasculitis syndrome in
children (73). S100A12 is more reliable than conventional parameters to determine response to gamma
globulin treatment. Patients with coronary artery abnormalities had higher initial and maximal S100A12 concentrations than patients without cardiac complications.
Accumulation of S100A8- and S100A9-expressing macrophages was found in antineutrophil cytoplasmic
antibody–positive renal vasculitis, especially in areas of
glomerular active lesions (74).
Chronic inflammatory bowel disease. S100A8/
S100A9-expressing phagocytes have been detected as
proinflammatory cells at sites of intestinal inflammation
(55,75). S100A8/S100A9 serum levels are useful in monitoring inflammation in patients with Crohn’s disease or
ulcerative colitis (75). S100A12 is another proinflammatory promoter of inflammatory bowel disease, since
blocking the interaction of S100A12 with RAGE reduced inflammation in a murine model of colitis (36).
S100A12 has been found to be massively expressed in
inflamed tissue from patients with active inflammatory
bowel disease. Serum concentrations of S100A12 correlate well with disease activity in individual patients (33).
Other autoimmune disorders. Elevated serum
concentrations of S100A8/S100A9 have also been found
in patients with Sjögren’s syndrome (76) and in patients
with systemic sclerosis (77). The function of S100 proteins in patients with these conditions remains undefined.
Opportunities for therapeutic intervention
As a consequence of the various proinflammatory properties of phagocyte-specific S100 proteins,
strategies targeting these molecules might represent a
novel option for antiinflammatory therapies. There is
evidence from animal models that the S100A12dependent activation of endothelium and the recruitment of inflammatory cells can be inhibited in vivo by
administration of either anti-S100A12 antibodies or
soluble RAGE constructs. These blocking agents also
inhibited acute inflammation in a murine model of
methylated bovine serum albumin–induced hypersensitivity, as well as chronic bowel inflammation in IL-10⫺/⫺
S100 PROTEINS IN ARTHRITIS AND AUTOIMMUNITY
mice. Most interestingly, S100A12 antagonists used in
mice immunized and challenged with bovine type II
collagen suppressed clinical and histologic evidence of
arthritis and diminished expression of TNF, IL-6, and
matrix metalloproteinases 3, 9, and 13 in affected tissues
(37,57). Thus, S100A12 is an attractive target for novel
antiinflammatory therapies in arthritis and autoimmune
disorders.
Data from in vitro studies indicated that the
propagation of transendothelial leukocyte migration mediated by S100A8/S100A9 may be inhibited by blocking
their binding to N-glycans on endothelial cells (40).
Another study tracked successful inhibition of S100A8/
S100A9-dependent inflammation in murine colitis by
blocking binding to cells via N-glycans in vivo (78). In
addition, blockade of lipopolysaccharide-induced proinflammatory effects of S100A8/S100A9 has been reported to be effective in a murine model (79).
Taking into account the abundance of S100A8
and S100A9 in the inflammatory processes, immunologic intervention targeting these proteins may be a
promising therapeutic option. However, due to their
high extracellular concentrations at sites of inflammation, it seems unlikely that conventional therapeutic
interventions, such as application of neutralizing antibodies or soluble receptors, will effectively block proinflammatory activities of S100A8 and S100A9 in the
clinical setting. The most promising approach may be
the inhibition of the release of these proteins, which is
strongly enhanced at sites of active inflammation. This
strategy may be very specific, since both proteins are
secreted via a so-called “alternative pathway.” The inhibition of this alternative transport mechanism will not
affect classic secretion of other proteins via endoplasmic
reticulum and Golgi complex, and thus may not be
complicated by major side effects. S100A8/S100A9 complex formation and phosphorylation of S100A9 seem to
be the important factors for intracellular transport during secretion and may, therefore, be primary targets for
S100A8- and S100A9-directed antiinflammatory strategies.
Conclusions
There is a large and continuously growing body of
evidence for the proinflammatory functions of S100A8,
S100A9, and S100A12 in the pathogenesis of arthritis
and autoinflammatory disorders. These proteins are
expressed and secreted by phagocytes within inflamed
tissue, and they interact specifically with molecules on
target cells. The subsequent activation of endothelium
3769
and immune cells results in the further recruitment of
leukocytes at sites of inflammation. In addition, direct
cytotoxic effects may contribute to tissue damage in
inflammatory lesions. The proinflammatory S100 proteins are valuable diagnostic marker proteins, due to a
close correlation with local inflammatory processes that
involve phagocyte activation. Diagnostic analyses of
these proteins provide additional information that is not
accessible from other markers of inflammation. In addition, proinflammatory S100 proteins are attractive therapeutic targets for immune interventions in the treatment of arthritis and autoimmune diseases.
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