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Originally published online as doi:10.1189/jlb.0306170 on August 30, 2006

Published online before print August 30, 2006
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(Journal of Leukocyte Biology. 2007;81:28-37.)
© 2007 by Society for Leukocyte Biology

S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules

Dirk Foell*,{dagger}, Helmut Wittkowski*,{dagger}, Thomas Vogl{dagger} and Johannes Roth*,{dagger},1

* Department of Pediatrics and
{dagger} Institute of Experimental Dermatology, University of Muenster, Muenster, Germany

1Correspondence: Department of Pediatrics, University of Muenster Albert-Schweitzer-Str. 33, Muenster D-48149, Germany. E-mail: rothj{at}uni-muenster.de

ABSTRACT

Damage-associated molecular pattern (DAMP) molecules have been introduced as important proinflammatory factors of innate immunity. One example known for many years to be expressed in cells of myeloid origin are phagocytic S100 proteins, which mediate inflammatory responses and recruit inflammatory cells to sites of tissue damage. An emerging concept of pattern recognition involves the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including S100 proteins. S100A8, S100A9, and S100A12 are found at high concentrations in inflamed tissue, where neutrophils and monocytes belong to the most abundant cell types. They exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo. Although S100A12 binds to RAGE, at least part of the proinflammatory effects of the S100A8/S100A9 complex depend upon interaction with other receptors. Because of the divergent expression patterns, the absence of S100A12 in rodents, the different interaction partners described, and the specific intracellular and extracellular effects reported for these proteins, it is important to differentiate between distinct S100 proteins rather than subsuming them with the term "S100/calgranulins." Analyzing the molecular basis of the specific effects exhibited by these proteins in greater detail bears the potential to elucidate important mechanisms of innate immunity, to establish valid biomarkers of phagocytic inflammation, and eventually to reveal novel targets for innovative anti-inflammatory therapies.

Key Words: myeloid related protein 8 (MRP8) • MRP14 • calgranulin • calprotectin • extracellular newly identified RAGE binding protein (EN-RAGE)

INTRODUCTION

The innate immune system has a key role in host defense and in initiating inflammation. Pharmaceuticals targeting innate immune mechanisms have been proven effective in the most relevant autoinflammatory disorders [1 , 2 ]. Recently, a novel group of molecules has been introduced as important proinflammatory factors of innate immunity. Because of their release by activated or damaged cells under conditions of cell stress, the terms "endokines," "alarmins," or damage-associated molecular pattern proteins (DAMPs) have been introduced for these molecules [3 ]. One example of this substance group are phagocytic S100 proteins, which mediate inflammatory responses [4 ]. An emerging concept of pattern recognition involves the multiligand receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including S100 proteins [5 6 7 ].

S100 proteins are calcium-binding proteins characterized by two calcium binding EF-hand motifs, which are connected by a central hinge region. The EF-hand comprises a calcium binding loop flanked by {alpha}-helices, thus resulting in a helix–loop–helix motif, which has been prototypically described for parvalbumine [8 ]. The first members of the S100 protein family were discovered more than 40 years ago and were purified from bovine brain. The protein complex was termed "S100" because of its solubility in 100% ammonium sulfate solution [9 ]. To date, more than 20 members of this protein family have been described [8 , 10 ]. Three S100 proteins are specifically linked to innate immune functions by their expression in cells of myeloid origin. S100A8 (also named calgranulin A; myeloid-related protein 8, MRP8), and S100A9 (calgranulin B; MRP14) are found in granulocytes, monocytes, and early differentiation stages of macrophages [11 12 13 14 15 ]. Expression of these proteins can also be induced in keratinocytes and epithelial cells under inflammatory conditions [16 , 17 ]. In contrast, S100A12 (calgranulin C; extracellular newly identified RAGE binding protein, EN-RAGE) is more restricted to granulocytes [18 ].

There is evidence that these phagocyte-specific S100 proteins are actively secreted via an alternative pathway bypassing the classical Golgi-route [19 ]. This mode of secretion is typical for DAMP-related factors, which have a role in cell homeostasis as intracellular molecules but turn into proinflammatory danger signals after release to the extracellular compartment due to cell damage, infections, or inflammation [20 ]. Various intra- and extracellular functions have been described for S100 proteins. Apart from binding calcium within the EF-hands, some S100 proteins bind zinc and copper. Some extracellular functions are related to antiinfectious host defense mechanisms. Antibacterial activity was shown for a 15-amino-acid peptide from the C terminus of S100A12 [21 ]. In addition, antiparasite activity has been reported for all calgranulin-family members [22 ]. Apart from these postulated functions in host defense, the main characteristics of the phagocyte-specific S100 proteins are related to proinflammatory mechanisms. They are significantly overexpressed at sites of inflammation [12 , 13 , 23 , 24 ], and there is a strong correlation of their serum concentrations to inflammation [25 ].

This review focuses on the phagocyte-specific S100 proteins as DAMPs and summarizes their role in inflammatory disorders.

S100A12 AND RAGE

S100A12 is overexpressed at sites of local inflammation, and serum concentrations correlate with individual disease activity in patients with inflammatory disorders (Fig. 1A 1B 1C ) [23 , 26 ]. Secretion of S100A12 by activated granulocytes has been demonstrated (Fig. 1D) [26 27 28 ]. S100A12 has been implicated in a novel inflammatory-axis, involving RAGE as a receptor-transducing proinflammatory signals in endothelium and cells of the immune system [5 , 29 ]. The description of the proinflammatory S100A12-RAGE axis was based on the finding that S100A12 extracted from bovine lungs bound to purified murine RAGE. Following that, bovine S100A12 was used to stimulate cells in vitro and to induce inflammation in mice in vivo [5 ]. In contrast to S100A12, S100A8, and S100A9 have not been shown to bind to RAGE.


Figure 1
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  		Figure 1. Expression of S100A12 in inflammatory bowel disease. (A) Immunohistochemical staining showing an extensive expression of S100A12 in inflamed colonic tissue of patients with active Crohn’s disease (CD). (B) Immunofluorescence microscopy of double-labeling studies with a-S100A12-Texas Red (red) and a-CD15-FITC (green) confirmed expression of S100A12 by infiltrating CD15-positive granulocytes. Double-labeled cells appear yellow. (C) S100A12 serum concentrations as determined by a specific ELISA system in 40 patients with CD, 34 patients with ulcerative colitis (UC), and 30 healthy controls. S100A12 levels are elevated during active disease. Box-plots show median, 25th and 75th percentile; error bars indicate 90% confidence intervals. (D) S100A12 concentration was determined in supernatants of cells either left untreated (w/o) or stimulated with TNF{alpha} for 30 min. There is a dose-dependent increase of S100A12 secretion after treatment with TNF{alpha}.

 
Interestingly, divergent pathways of gene expression are activated by different RAGE ligands [30 ]. Activation of the RAGE pathway has been suggested to be important in wound healing, tumor outgrowth, systemic amyloidosis, and inflammation [5 , 29 , 31 , 32 ], but in other experimental settings, this could not be confirmed by using LPS-free ligands [33 , 34 ]. Although triggering of various intracellular signaling pathways can be seen in response to stimulation with different ligands, no adaptor protein for the transduction of intracellular signals has been identified. The strongest evidence for independent RAGE signaling pathways has been obtained by blocking proinflammatory effects with added RAGE constructs composed of the extracellular receptor domain. It is hypothesized that this soluble RAGE acts by neutralizing proinflammatory ligands. In addition, inflammatory responses could be minimized by adding anti-S100A12 or anti-RAGE antibodies [5 ]. However, the effects of anti-S100A12 antibodies in murine models of inflammation are hard to interpret, as mice do not express this protein [35 , 36 ]. Neutralizing proinflammatory DAMPs with soluble RAGE is on the other hand no proof of RAGE as the sole receptor involved in S100A12 effects. This is even more supported by findings obtained with RAGE–/– mice, in which inflammation could be further inhibited by adding soluble RAGE. In these animals, proinflammatory effects by RAGE ligands must therefore rely upon other receptor pathways, which can be inhibited by neutralizing circulating ligands [37 ].

Huttunen and Rauvala suggested that the residues 3-39 of S100A12 represent the binding site for RAGE, as this peptide shares some sequence homology with the C-terminal region of another RAGE ligand, high-mobility group box 1 protein (HMGB1). This region serves as the RAGE binding motif in HMGB1 [38 ]. However, the exact nature of S100A12-RAGE interactions still needs to be defined. Although there is no doubt that S100A12 binds to RAGE, it is still not clear to date how RAGE contributes to the proinflammatory effects. RAGE could be both a pattern recognition receptor for DAMPs or a scavenger receptor, which may have a primary role in binding proinflammatory ligands, either to recruit these molecules to other signaling receptors on the cell surface or to block the action of these ligands [34 ].

S100A12 has been described to enhance the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelium (Fig. 2C ). Furthermore, nuclear factor (NF){kappa}B driven up-regulation of the expression of proinflammatory cytokines, such as tumor necrosis factor {alpha} (TNF{alpha}), by other inflammatory cells, has been reported after S100A12 stimulation [5 ]. Furthermore, it was reported by using antibodies generated against bovine S100A12 that mice reveal overexpression of S100A12 during states of inflammation [39 ]. Taking into account the sequence homology of S100 proteins and the cross-reactivity of antibodies generated against S100 proteins, this can only be explained by low specificity of used antibodies, because there is convincing evidence for the absence of S100A12 in mice [35 , 36 , 40 ]. It has been suggested that a duplication and divergence of S100A8 in humans, compared with rodents, have permitted the separation of two functions. In mice, S100A8 is abundant and acts chemotactically within the picomolar range [41 ]. In humans, S100A12 may chiefly act as a proinflammatory mediator by binding to and activating cells expressing RAGE [42 ].


Figure 2
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  		Figure 2. Secretion and proinflammatory activities of S100A8/S100A9 and S100A12. (A) S100A8/S100A9 are specifically released during interaction of activated monocytes with TNF-stimulated endothelial cells. Secretion of S100A8/S100A9 is dependent on parallel activation of protein kinase C (PKC) and elevation of intracellular calcium concentrations. Extracellular S100A8 and S100A9 exhibit autokrine effects on phagocytes by up-regulation of adhesion receptor CD11b/CD18, which induces firm adhesion of phagocytes to endothelial cells (ECs). (B) S100A8 and S100A9 bind specifically to ECs and induce a thrombogenic and inflammatory response by increasing the expression of proinflammatory chemokines like IL-8 and adhesion molecule ICAM-1. In addition, S100A8 and S100A9 increase vascular permeability by down-regulation of membrane expression of EC junction proteins and molecules involved in monolayer integrity. (C) S100A12 is released either in inflamed tissue or in the bloodstream by activated granulocytes. Secreted S100A12 binds to RAGE on ECs. This leads to enhanced expression of ICAM-1. The additional chemotactic properties of S100A12 contribute to augmented extravasation of granulocytes and monocytes to sites of inflammation.

 
S100A8/S100A9

Structural data are meanwhile available from nearly all S100 proteins in the presence and absence of calcium [8 ]. Typically, one observes a tightly packed homodimer, which consists of two subunits composed of two helix–loop–helix regions and is separated by the central hinge region with the exception of monomeric calbindin. Calcium ion binding induces conformational changes enabling the S100 protein to recognize and modulate the target. In contrast to most other S100 proteins S100A8 and S100A9 are also able to heterodimerize. For murine S100A8 and S100A9, it was found that both proteins are able to form homodimers as well as heterodimers.

The situation for human S100A8 and S100A9 is rather complex. Beside homodimers and heterodimers, also tetramers (S100A8/S100A9)2 have been described [43 ]. In the presence of calcium, heterotetramers consisting of two molecules of S100A8 and two molecules of S100A9 were formed. However, in the absence of calcium, the heterodimer is the preferred form, and no homodimers could be detected. A trimer of S100A8/S100A92 has been suggested by gel chromatography and was referred to as "calprotectin," but this finding was obviously based on an artifact since trimer formation is contradicted by structural data obtained by NMR analysis [44 , 45 ].

S100A12 INTERFERENCE WITH S100A8/S100A9

The combined expression of all three S100 proteins in granulocytes and the simultaneous translocation of S100A12, S100A8, and S100A9 from the cytosol to cytoskeletal and membrane structures in a calcium-dependent manner raised the question of possible interactions with each other. However, we found no evidence for direct protein–protein interactions of S100A12 with either S100A8 or S100A9 or the heterodimer by chemical cross-linking, density gradient centrifugation, mass spectrometric measurements, or yeast two-hybrid detection. Thus, S100A12 acts individually during calcium-dependent signaling, independent from S100A8 and S100A9 [18 ].

S100A8/S100A9 AND CYTOSKELETON

A couple of studies showed that S100A8/S100A9 is obviously able to interact with components of the cytoskeleton of the cell in a calcium-dependent manner. Immunogold labeling experiments revealed a clear colocalization of S100A8/S100A9 complexes with the type III intermediate filament vimentin [46 ], as well as with microtubules [19 ] at elevated calcium concentrations in human monocytes. A calcium-dependent binding of S100A8/S100A9 to keratin filaments was additionally observed in TR146 cells [47 ]. In human neutrophils, S100A9 was associated with cortical F-actin in small amounts, whereas in vitro biochemical studies showed a direct association of S100A8/S100A9 to F-actin [48 ].

However, a functional correlation could be shown only for the interaction of S100A8/S100A9 and microtubules [49 ]. As described above, S100A8/S100A9 forms tetramers in the presence of calcium. The tetramers bind directly to microtubules and also increase the rate constant of tubulin polymerization markedly. The underlying molecular mechanism is obviously a bundling or bridging of microtubule and, thereby, a stabilization of tubulin filaments by S100A8/S100A9 tetramers. In contrast, complexes containing a S100A9 mutant unable to tetramerize show no association with bundles of microtubules [50 ]. Edgeworth et al. first identified a phosphorylation site of S100A9 [51 ]. S100A9 is specifically phosphorylated by p38 mitogen-activated protein kinase (MAPK) at threonine 113. This phosphorylation inhibits S100A8/S100A9-induced tubulin polymerization. The biological relevance of these findings is confirmed by the fact that MAPK p38 fails to stimulate migration of S100A9–/– granulocytes in vitro and S100A9–/– mice show a diminished recruitment of granulocytes into the granulation tissue during wound healing in vivo. S100A9–/– granulocytes contain significantly less polymerized tubulin, which subsequently results in minor activation of Rac1 and Cdc42 after stimulation of p38 MAPK. Phosphorylation of S100A9 by p38 MAPK depends on calcium binding. Thus, the complex of S100A8/S100A9 is the first characterized molecular target integrating MAPK and calcium-dependent signals during migration of phagocytes [49 ]. This new intracellular function of S100A8/S100A9, the modulation of the tubulin-dependent cytoskeleton during migration of phagocytes, could be one molecular basis of the unusual rapid ability of monocytes and granulocytes to rearrange the cytoskeleton.

SECRETION OF S100A8/S100A9

Noncovalently associated S100A8/S100A9 complexes are secreted by activated phagocytes during inflammatory processes. Secretion of S100A8/S100A9 is induced during contact of phagocytes with inflamed endothelium [52 ]. Both S100 proteins lack structural requirements for classical transport via the endoplasmic reticulum and Golgi complex. However, release of S100A8 and S100A9 by human monocytes is a specific and energy-dependent process [19 ]. Secretion involves activation of protein kinase C (PKC) and active metabolism of the microtubule network (Fig. 2A) . Release of S100A8 and S100A9 is independent from de novo synthesis and is rather associated with down-regulation of mRNA expression of both genes, suggesting that extracellular signaling via S100A8/S100A9 is restricted to early differentiation stages of monocytes/macrophages [19 , 52 ]. An extraordinarily high abundance of these proteins in extracellular fluids defines a novel, recently identified inflammatory disorder showing recurrent infections, hepatosplenomegaly, anemia, vasculitis, and systemic inflammation, which underscores the role of extracellular S100A8/S100A9 in inflammation [53 ].

CHEMOTACTIC ACTIVITY

Murine S100A8 has been described earlier to stimulate a chemotactic response in phagocytes [54 , 55 ]. The biological relevance of a chemotactic activity, however, has been questioned by the fact that mice overexpressing these S100 proteins in epidermal cells of the skin show no dermal infiltration by leukocytes [56 ]. The concentrations of human S100A8 used in chemotaxis assays in vitro have been 100–10,000-fold lower compared with those levels found in serum of healthy controls or of patients suffering from inflammatory diseases [57 , 58 ]. It is, therefore, highly questionable whether the reported chemotactic effects observed in vitro are of biological relevance in vivo.

ACTIVATION OF ENDOTHELIAL CELLS

After release by activated phagocytes, S100A8 and S100A9 bind specifically to endothelial cells. Potential ligands on endothelial cells (ECs) are heparan sulfate proteoglycans or carboxylated N-glycans expressed by ECs after activation [59 , 60 ]. Blocking the interaction of S100A8 and S100A9 with carboxylated N-glycans on endothelium results in inhibition of leukocyte extravasation in a murine model [60 ]. The significant role of S100A8 and S100A9 for leukocyte recruitment is further underscored by the finding that S100A8 and S100A9 increases the binding capacity of the integrin receptor CD11b-CD18 on leukocytes to ICAM-1 on endothelium [61 ].

S100A8 and S100A9 induce a thrombogenic and inflammatory response in human ECs. Thrombospondin 1 is up-regulated by S100A8/S100A9 in ECs. This protein is considered to mediate platelet aggregation [62 ]. Functionally, S100A8/S100A9 showed a specific thrombogenic reaction in ECs leading to platelet adhesion and aggregation. In contrast, we found no direct activating influence of S100A8/S100A9 on platelets [63 ].

In addition, S100A8 and S100A9 induce a number of proinflammatory chemokines, as well as adhesion molecules like VCAM-1 and ICAM-1. Furthermore, enzymes of the mitochondrial superoxide metabolism were up-regulated [63 ]. Keeping in mind the conditions leading to secretion of S100A8/S100A9, these findings point to a novel positive feedback mechanism by which phagocytes promote further recruitment of leukocytes to sites of inflammatory reactions [19 , 52 ].

Cell surface receptors mediating monolayer formation and cell junction-associated proteins were down-regulated in ECs after treatment with S100A8/S100A9. A negative effect of these proteins on endothelial monolayer integrity was confirmed by a dose-dependent increase of the endothelial permeability and a parallel loss of endothelial cell-cell contacts and cell junction proteins [63 ]. Thus, S100A8 and S100A9 induce a specific inflammatory pattern in ECs, which is characterized by the induction of a prothrombotic and proinflammatory response and an increased vascular permeability (Fig. 2B) .

INDIVIDUAL FUNCTIONS OF DIFFERENT S100 PROTEINS

Because of their properties, S100A8, S100A9, and S100A12 can be assigned to the group of DAMPs. Like other DAMPs, for example, HMGB1, these S100 proteins exhibit a double life: As intracellular calcium-binding molecules, they have a role in migration and cytoskeletal metabolism. After release into the extracellular space, due to cell damage or activation of phagocytes, they become danger signals that activate immune cells and vascular endothelium. As mentioned above, S100A12 has been shown to exhibit its proinflammatory activities via interaction with the multiligand receptor RAGE [5 ]. Some authors suggest that all S100 proteins act via RAGE [64 ]. However, this hypothesis has not been experimentally proven so far. Currently available data suggest that signaling, independent from RAGE, is responsible for at least some S100A8/S100A9-mediated effects on phagocytes. The S100 family comprises more than 20 members, and extracellular functions have been shown for at least six S100 proteins so far. In our opinion, binding of all of these S100 proteins to the same receptor cannot explain the diversity of effects induced by individual S100 proteins in different target cells.

The amino acid sequence of human S100A12 shares 40, 46, 66, and 70% identity with human S100A8, human S100A9, bovine S100A12, and pig S100A12, respectively [36 ]. The substantial structural homology of these proteins make the generation of specific antibodies difficult. There is a strong cross-reactivity between antibodies directed against these three human proteins, thus interfering with specific protein detection. This fact is underestimated in most studies on calgranulins, which can only be specifically determined by using antibodies proven to exhibit minimal cross-reactivity. The currently available data indicate that the three phagocyte-specific S100-proteins S100A8, S100A9, and S100A12 exhibit specific functions via interaction with different receptor systems. It is therefore not adequate to use global terms like "S100/Calgranulins" in this context, which does not differentiate between individual and functionally different molecules (Table 1 ).


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  		Table 1. Differences Between S100A8/S100A9 and S100A12

 
FUNCTIONAL DIFFERENCES BETWEEN MICE AND MAN

S100A8 and S100A9 show an almost identical expression pattern in the human and murine systems [65 ]. Mouse models have been used in approaches to elucidate the functions of phagocyte-specific S100-proteins. Gene deletion of S100A8 in the mouse results in rapid embryo resorption by day 9.5 of development, indicating an important function in embryogenesis [55 ]. Gene deletion for S100A9 results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro, which is paralleled by a diminished recruitment of granulocytes into the granulation tissue during wound healing in vivo [49 , 66 ].

There is evidence that a functional S100A12 gene is not present in the murine genome [35 ]. This gene seems to be disrupted during rodent evolution [36 , 40 ]. It is hypothesized that murine S100A8 compensates for lacking S100A12 in mice. Previous studies demonstrated a potent chemotactic activity of mS100A8 for monocytes and neutrophils in vitro. This activity was not confirmed with human S100A8, which has only 57% amino acid identity. In contrast, S100A12 has been assigned a potent monocyte chemoattractant [42 ]. The functional and sequence divergence suggests complex evolution of the S100 family in mammals. It is hypothesized that mS100A8 and human S100A12 may be functional chemoattractant equivalents and that S100A12 may have arisen by duplication of either human S100A8 or human S100A9 [36 ]. It seems likely that the S100A12 homodimer may overtake some inflammatory functions of murine S100A8 homodimers in the human system [4 ]. However, further research is necessary to answer this question using exclusively proteins of the homologues species. It is no longer appropriate to draw conclusions from functional experiments mixing up components of different species.

S100 PROTEINS IN HUMAN DISEASES

A detailed overview of associations between S100A8/S100A9 or S100A12 and arthritis and a characterization of these S100 proteins as biomarkers of inflammation has been recently published [23 , 25 ]. Reported disease associations are also summarized in Tables 2 and 3 .


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  		Table 2. Disease Associations of S100A8/S100A9

 

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  		Table 3. Disease Associations of S100A12

 
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 inflammatory lesions in the synovium [12 , 13 ]. Early recruited phagocytes expressing S100A8/S100A9 have been found in the sublining layer of inflamed synovial tissue [67 ]. There is evidence for release of S100A8/S100A9 in synovial fluid obtained from inflamed joints as reflected by ~10-fold higher concentrations in synovial fluid than in the serum obtained in parallel from individual patients [68 69 70 ]. Numerous studies on serum levels of S100A8/S100A9 in patients with RA and psoriatic arthritis (PsA) have confirmed the excellent correlation of serum S100A8/S100A9 concentrations with the inflammatory activity of arthritis superior to C-reactive protein level and erythrocyte sedimentation rate [70 , 71 ].

More recently, S100A12 levels have been found to be increased in the synovial fluid and serum of patients with RA and PsA but undetectable in osteoarthritis [72 ]. S100A12 is strongly expressed in inflamed synovial tissue, whereas it is nearly undetectable in synovia of controls or patients after successful treatment [73 ]. Inflamed synovium of RA patients was found to contain S100A12-positive neutrophils in the sublining and interstitial region, often surrounding the perivascular tissue but to a lesser extent in the synovial lining layer [74 ]. Serum levels of S100A12 correlate well with disease activity [73 ]. The expression pattern of S100A8/S100A9 and S100A12 in PsA is clearly distinct from that in RA, as these molecules are predominantly found in perivascular areas of the synovial sublining layer. This expression is significantly reduced in serum and synovium from patients with PsA after successful treatment with methotrexate [70 , 73 ].

Juvenile idiopathic arthritis
S100A8, S100A9, and S100A12 have also been detected in serum and synovial fluid of patients with juvenile idopathic arthritis (JIA). S100A8/S100A9 serum concentrations correlated well with individual disease activity in long-term studies in children [52 , 68 , 75 ]. Preliminary studies suggested that patients with clinically inactive JIA, but elevated levels of S100A8/S100A9 or S100A12, may be at risk for disease flareups [75 ].

Children with systemic onset of JIA (SOJIA), characterized by massive neutrophil activation, have serum concentrations of phagocyte-specific S100 proteins up to 20-fold higher than those found in sepsis or other inflammatory disorders [75 76 77 ]. Therefore, S100A8/S100A9 and S100A12 may be useful in distinguishing SOJIA from systemic infections, which represent the most important differential diagnosis. Interestingly, patients with SOJIA show also an extensive expression of S100A8/S100A9 in their dermal epithelium, indicating for the first time an active role of this cell type during the initiation of a systemic autoimmune disorder [78 ].

Systemic autoimmune diseases
In dermatomyositis, polymyositis, and inclusion body myositis, there is a clear association of S100A8 and S100A9 expression by infiltrating macrophages with degeneration of myofibers. In vitro data indicated that activated macrophages promote destruction and impair regeneration of myocytes in the course of inflammatory myopathies via release of these S100-proteins [79 ].

In systemic lupus erythematosus (SLE), elevated serum concentrations of S100A8/S100A9 have been found that correlated significantly with the SLE disease activity index [80 ]. Immunohistochemical analysis of renal biopsies demonstrates that expression of S100A8/S100A9 by infiltrating macrophages in the glomeruli of SLE-patients correlated well with the severity of the inflammatory process [81 ].

In Kawasaki disease, elevated serum concentrations of S100A12 correlated more reliably than conventional parameters with the inflammatory disease activity of this acute vasculitis syndrome in childhood [28 , 82 ]. Patients with coronary artery abnormalities had higher initial and maximal S100A12 concentrations and persistent elevated levels of S100A8/S100A9 in comparison to patients without cardiac complications [82 , 83 ]. Accumulation of S100A8 and S100A9 expressing macrophages was found in ANCA+ renal vasculitis, especially in areas of glomerular active lesions [84 ]. An expression of S100A8/S100A9 and S100A12 at sites of inflammation and elevated serum levels compared with healthy controls has also been described in giant cell arteritis [24 ].

Chronic inflammatory bowel disease
S100A8/S100A9 expressing phagocytes have been detected as proinflammatory cells at sites of intestinal inflammation [85 , 86 ]. Measurement of S100A8/S100A9 in feces has converted into a reliable method to distinguish inflammatory bowel disease (IBD) patients from patients without chronic intestinal inflammation and is together with S100A8/S100A9 serum levels useful in monitoring inflammation in patients with Crohn’s disease or ulcerative colitis [87 , 88 ]. S100A12 has been found to be massively expressed in inflamed tissue from patients with active inflammatory bowel disease (Fig. 1A and 1B) . Serum concentrations of S100A12 correlate well with disease activity in individual patients [26 ].

Other diseases
Contribution of the S100 proteins to vasculitis-induced pathologies is mentioned above, but also the role of S100 proteins in atherosclerosis has been investigated in recent years. Enhanced expression of S100 proteins in vascular inflammation of diabetic apolipoprotein E–/– mice has been reported [39 , 89 ]. Recently, S100A8/S100A9 protein and mRNA could be found in macrophages and foam cells of human atheroma [90 ]. Elevated S100A12 serum concentrations in type 2 diabetes have been described and could contribute to vascular inflammatory responses via endothelial activation and consecutive atherosclerotic changes [91 ]. A role of S100 proteins as biomarkers of inflammation has been described in a variety of infectious conditions.

CONCLUDING REMARKS

S100A8, S100A9, and S100A12 are calcium-binding proteins expressed in the cytoplasm of phagocytes and overexpressed at local sites of inflammation. They exert independent intra- and extracellular effects. After release by phagocytes in response to cell stress, they turn into DAMPs. It is notable that these proteins are found in high concentrations in inflamed tissue, where neutrophils and monocytes belong to the most abundant cell types. They exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo.

There is a substantial structural homology between S100A8, S100A9, and S100A12, which has to be addressed in protein detection studies. Although sharing many similar characteristics, the divergent expression patterns, the different interaction partners and receptor structures described, and the specific intra- and extracellular effects reported for these proteins have to be acknowledged. The absence of the S100A12 gene in laboratory rodents makes studies using these animals as model systems difficult to interpret. In particular, using S100A12 in a species that does not normally express this protein makes it difficult to relate particular functions to the human proteins. Therefore, the use of mouse studies for investigating S100A12 effects is of limited use.

Taking in account the different characteristics and functions of S100A8, S100A9, and S100A12, it is crucial to differentiate between distinct S100 proteins rather than subsuming them with the term "S100/calgranulins." Thoroughly analyzing the molecular basis of the specific effects of these proteins in greater detail may guide important mechanisms of innate immunity. These DAMPs can serve as valid biomarkers of phagocytic driven inflammation, and they may eventually be attractive targets for novel anti-inflammatory therapies.

Received March 5, 2006; revised May 11, 2006; accepted May 13, 2006.

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