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Originally published online as doi:10.1189/jlb.1008647 on May 18, 2009

Published online before print May 18, 2009
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(Journal of Leukocyte Biology. 2009;86:557-566.)
© 2009 Society for Leukocyte Biology

The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer

Jan M. Ehrchen*,{dagger},{ddagger}, Cord Sunderkötter{dagger},{ddagger}, Dirk Foell*,{ddagger}, Thomas Vogl*,{ddagger} and Johannes Roth*,{ddagger},1

* Institute of Immunology,
{dagger} Department of Dermatology, and
{ddagger} Interdisciplinary Center for Clinical Research, University of Muenster, Muenster, Germany

1. Correspondence: Institute of Immunology, University of Muenster, Roentgenstrasse 21, D-48149 Muenster, Germany. E-mail: rothj{at}uni-muenster.de


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ABSTRACT
 
The innate immune system is crucial for initiation and amplification of inflammatory responses. During this process, phagocytes are activated by PAMPs that are recognized by PRRs. Phagocytes are also activated by endogenous danger signals called alarmins or DAMPs via partly specific, partly common PRRs. Two members of the S100 protein family, S100A8 and S100A9, have been identified recently as important endogenous DAMPs. The complex of S100A8 and S100A9 (also called calprotectin) is actively secreted during the stress response of phagocytes. The association of inflammation and S100A8/S100A9 was discovered more than 20 years ago, but only now are the molecular mechanisms involved in danger signaling by extracellular S100A8/S100A9 beginning to emerge. Taking advantage of mice lacking the functional S100A8/S100A9 complex, these molecules have been identified as endogenous activators of TLR4 and have been shown to promote lethal, endotoxin-induced shock. Importantly, S100A8/S100A9 is not only involved in promoting the inflammatory response in infections but was also identified as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. This proinflammatory action of S100A8/S100A9 involves autocrine and paracrine mechanisms in phagocytes, endothelium, and other cells. As a net result, extravasation of leukocytes into inflamed tissues and their subsequent activation are increased. Thus, S100A8/S100A9 plays a pivotal role during amplification of inflammation and represents a promising new therapeutic target.

Key Words: myeloid related proteins • calgranulin • MRP8 • MRP14


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Introduction
 
The innate immune system represents the first line of defense against invading pathogens and other external harmful agents. To fulfill this function, cells of the innate immune system are equipped with receptors that recognize PAMPs. The NOD and TLR families are prominent examples for these PRRs [1 , 2 ]. Activation of PRRs results in secretion of cytokines and chemokines and thus, in initiation and amplification of inflammation. Moreover, it has become increasingly evident that the innate inflammatory response is also modified by endogenous ligands called alarmins or DAMPs [3 4 5 6 7 8 9 ]. These DAMPs are intracellular molecules primarily involved in cell homeostasis but can also act as extracellular danger signals when released as a result of cell damage or secreted by activated cells. Like PAMPs, DAMPs are recognized by PRRs. Interestingly, some receptors such as the TLR4 seem to be able to recognize PAMPs as well as DAMPs [8 , 9 ].

Recently, S100A8 and S100A9, two members of the S100 protein family, have been identified as important DAMPs released by activated phagocytes and recognized by TLR4 on monocytes [10 ].

S100 proteins were isolated originally from bovine brain tissue and termed "S100" as a result of their solubility in 100% ammonium sulfate [11 ]. To date, the S100 family comprises more than 20 members. Some S100 proteins are linked directly to the innate immune system and have been characterized recently as endogenous DAMPs: S100A7, S100A15 [12 ], S100A12, S100A8, and S100A9 (for review, see refs. [6 , 7 , 13 ]). S100A12 is expressed mainly by granulocytes and under distinct conditions in subsets of activated monocytes and macrophages [14 ] and has been described as endogenous ligand of the multiligand RAGE [7 ]. S100A8 (also termed MRP8) and S100A9 (MRP14) exist mainly as a S100A8/S100A9 heterodimer (termed calprotectin) and are expressed by granulocytes, monocytes, and early differentiation states of macrophages. Moreover, S100A8/S100A9 expression is inducible in mature macrophages, osteoclasts, and keratinocytes. Expression in fibroblasts and microvascular endothelial cells has been described [15 16 17 ]. A biological relevance of these findings, however, has to be confirmed still. This review focuses on the recent advances in understanding the function of S100A8 and S100A9 as endogenous DAMPs.


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STRUCTURE OF S100A8 AND S100A9
 
These proteins belong to the family of S100 proteins, which are calcium-binding cytosolic molecules characterized by two calcium-binding EF hands with different affinities for calcium connected by a central hinge region. The EF-hand motifs are composed of two {alpha}-helices flanking a central calcium-binding loop, thus resulting in a classical helix–loop–helix motif [18 ]. Like most S100 proteins, murine S100A8 and S100A9 are able to form homodimers, but they also exist as heterodimers.

Human S100A8 and S100A9 form heterodimers and even higher oligomeric forms. Recently, a tetramer of S100A8 and S100A9 was described. Tetramer formation was strictly dependent on the presence of calcium, and in the absence of calcium, the heterodimer is the preferred form of human S100A8 and S100A9 [19 20 21 ]. The presence of the human homodimers is still a matter of debate.


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S100A8/S100A9 AND CYTOSKELETON
 
S100A8/S100A9 interacts with components of the cytoskeleton in a calcium-dependent manner. Specific binding of S100A8/S100A9 to microtubules, vimentin, keratin, and actin filaments has been described [22 23 24 25 26 ]. So far, a functional correlation was only found for the interaction of S100A8/S100A9 with microtubules. In the presence of calcium, S100A8/S100A9 tetramers promote tubulin polymerization and bundle microtubules, resulting in stabilization of tubulin filaments [23 ]. S100A8/S100A9 complexes, containing a mutated form of S100A9 unable to form tetramers, showed no association with bundles of microtubules [27 ].

S100A9 can be modified further by p38 MAPK-dependent threonine phosphorylation [23 ], which inhibits S100A8/S100A9-dependent tubulin polymerization. Phosphorylation of S100A9 depends on calcium binding. Thus, the interaction of S100A8/S100A9 with microtubules is regulated by MAPK and calcium-dependent signaling pathways, which are critical for phagocyte migration. Indeed, S100A9–/– mice that lack a functional S100A8/S100A9 complex show diminished granulocyte migration and wound healing, and activation of MAPK p38 was unable to stimulate migration of granulocytes from S100A9–/– mice that contain significantly less polymerized as well as cytosolic tubulin [23 ]. Thus, S100A8/S100A9 is critically involved in modulation of the tubulin-dependent cytoskeleton during phagocyte migration and could therefore represent a molecular basis for the rapid ability of these cells to rearrange the cytoskeleton.


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EXTRACELLULAR S100A8/S100A9
 
The double life of S100A8/S100A9, as an intracellular differentiation marker for phagocytes and as an extracellular protein complex associated with inflammatory processes, was known long before the concept of DAMPs, as endogenous danger signals were developed. Over the past 15 years, S100A8/S100A9 has evolved as an excellent biomarker of inflammatory processes, especially in rheumathoid arthritis, juvenile idiopathic arthritis, and inflammatory bowel disease [7 , 13 ]. In addition, S100A8/S100A9 serum levels have been identified recently as an independent risk predictor for cardiovascular events in healthy individuals [28 ] and as a prime candidate for the detection of unstable versus stable coronary artery plaques [29 ] and myocardial infarction in acute coronary syndrome [30 ]. Detailed overviews of S100A8/S100A9 as biomarkers for inflammation have been published recently [6 , 7 , 13 , 31 ]. Associations of S100A8/S100A9 and human disease are also summarized in Table 1 . Consequently, the idea that S100A8/S100A9 is not only a useful marker of inflammation but also plays a pivotal role in the pathogenesis of inflammatory disorders became more and more intriguing. This line of thought received a further boost by the discovery of a new disease characterized by recurrent infections, hepato-splenomegaly, anemia, vasculopathie, concomitant cutaneous ulcers, and systemic inflammation, which were defined by extraordinarily high levels of S100A8/S100A9 in extracellular fluids, up to 1.4–6.5 g/l (reference range <1 mg/l) [61 , 62 ].


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  		Table 1. Recent Associations of S100A8/S100A9 and Human Diseases

Thus, the question arises of how S100A8/S100A9 gains access to the extracellular compartment.

As cytoplasmic proteins S100A8 and S100A9 lack a leader signal, they are not secreted via the classical Golgi-associated pathway. However, there is good evidence that active nonclassical secretion rather than passive release from necrotic cells is the major physiological source for extracellular S100A8/S100A9, which is secreted by phagocytes activated by inflammatory cytokines [22 ]. The interaction of activated endothelium with phagocytes was described as an important stimulus for S100A8/S100A9 secretion [36 ]. The release of S100A8/S100A9 by human monocytes is a specific and energy-dependent process [22 ]. Secretion of S100A8/S100A9 involves activation of PKC and is dependent on a functional microtubule network but does not require de novo protein synthesis.

These results indicate that S100A8/S100A9 represents a danger signal, which is actively put into action by sentinel cells sensing danger rather than being passively released once tissue damage has occurred. In this way, it clearly reflects the evolutionary transition of DAMPs from passively released intracellular proteins that are recognized as danger signals by the innate immune system toward actively secreted cytokines or chemokines. Indeed, the classical cytokine IL-1{alpha} was reported to exert some intracellular functions and thus, was also described as a DAMP protein [63 ].

Nonclassical secretion of S100A8/S100A9 resembles, in some aspect, the Golgi-independent secretion of cytokines such as IL-1β, IL-1{alpha}, and FGF1 [64 ]. However, although secretion of S100A8/S100A9 can be inhibited by microtubule-depolymerizing drugs, this is not the case for IL-1β [22 ]. Moreover, uncouplers of oxidative phosphorylation increased release of IL-1β [65 ], and they inhibited secretion of S100A8/S100A9. Recently, caspase-1 has been identified not only as an activator of IL-1β but also as involved in nonclassical secretion of IL-1{alpha}/FGF1 and other proinflammatory mediators in UV type B-stimulated keratinocytes [66 ]. S100A8/S100A9 was not identified as a caspase-1 target in this study. Thus, secretion of S100A8/S100A9 appears to follow an alternative secretory pathway independent from the IL-1β type and IL-1{alpha}/FGF1 type. Functional similarities between cytokines such as IL-1β, however, remain, especially with respect to the corresponding receptors. The IL-1βR and the recently discovered S100A8/S100A9 receptor TLR4 [10 ] belong to the same receptor family, which is defined by a common intracellular Toll-IL-1R domain. Moreover, the signaling cascades activated by IL-1RI and TLR4 are similar, including action of the adaptor protein MyD88 and NF-{kappa}B activation [67 ].


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ACTIVATION OF ENDOTHELIAL CELLS
 
S100A8/S100A9 binds specifically to endothelial cells by a mechanism involving heparan sulfate proteoglycans and novel carboxylated glycans [68 , 69 ]. Using a whole genome expression-profiling approach, Viemann et al. [70 ] characterized the S100A8/S100A9-induced expression pattern of HMEC-1. Bioinformatical analysis and independent functional assays revealed that S100A8/S100A9 induces a proinflammatory and thrombogenic response in endothelial cells, which is characterized by induction of proinflammatory cytokines and adhesion molecules. S100A8/S100A9 stimulation resulted in a loss of cell–cell contacts and an increased permeability of endothelial monolayers in vitro [70 ]. As the S100A9 monomer has been described to increase the binding affinity of the integrin receptor CD11b/CD18 on neutrophil granulocytes and thus, adhesion of these cells to endothelium, the net result of S100A8/S100A9 action should be an increased leukocyte extravasation during inflammation [71 ]. Recruitment of leukocytes is an important function of DAMP molecules, which additionally highlights the potential of S100A8/S100A9 as an endogenous danger signal.

Further bioinformatical analysis of the S100A8/S100A9-dependent gene expression pattern in endothelial cells revealed that apoptosis-related genes were expressed differentially [72 ]. Strikingly, antiapoptotic genes were inhibited, and potent proinflammatory genes such as p53, bak, and bax were induced. In agreement with these results, prolonged stimulation of HMEC-1 cells with S100A8/S100A9 resulted in apoptosis and to a certain degree, necrosis of these cells [72 ]. Caspase-9 and caspase-3 were also involved in S100A8/S100A9-mediated apoptosis, indicating activation of the mitochondrial apoptotic pathway, and the death receptor-mediated pathway was not affected. DNA fragmentation, however, was largely independent from the mitochondrial pathway in S100A8/S100A9-mediated apoptosis, indicating that besides the mitochondrial pathway, other mechanisms are involved in S100A8/S100A9-mediated cell death. Importantly, induction of cell death by S100A8/S100A9 occurred secondary to the impairment of endothelial integrity and loss of cell junction proteins. Thus, loss of survival signals from neighboring cells could be critically involved in S100A8/S100A9-mediated endothelial cell death. As S100A8/S100A9 is released in high amounts at sites of inflammation, S100A8/S100A9-induced endothelial damage might be a critical component in the pathomechanisms of vasculitis or vasculopathies and other inflammatory disorders associated with endothelial dysfunction and increased secretion of S100A8/S100A9 [61 ].


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S100A8/S100A9 IN INFECTION: S100A8/S100A9 IS AN ENDOGENOUS TLR4 LIGAND
 
To fulfill its proposed function as an endogenous DAMP protein, extracellular S100A8/S100A9 has to be recognized by PRRs. Binding of S100A8/S100A9 to diverse cell-surface proteins has been described. S100A8/S100A9 binds to heparan sulfate proteoglycan and carboxylated N-glycans on endothelial cells [68 , 69 ] and to carboxylated N-glycans on chondrocytes [73 ]. The multiligand receptor RAGE was also repeatedly proposed to act as a S100A8/S100A9 receptor [74 , 75 ]. However, carboxylated N-glycans expressed by RAGE may be responsible for S100A8/S100A9 binding, and the question of whether RAGE is able to mediate S100A8/S100A9 signal transduction directly or act as one of multiple S100A8/S100A9-binding complexes on the cell surface is still controversial [75 ].

An important contribution toward understanding S100A8/S100A9-mediated signal transduction was achieved by an unbiased whole genome expression study analyzing basal as well as endotoxin (LPS)-stimulated gene expression in bone marrow cells from wild-type and S100A9 gene-deficient (S100A9–/–) mice [10 ]. In leukocytes of S100A9–/– mice, protein expression of S100A8, in contrast to normal mRNA levels, is also abolished, resulting in a functional double knockout. This is probably a result of a higher turnover of S100A8 in the absence of its binding partner S100A9 [23 , 32 ]. Although the basal gene expression patterns were similar, S100A9–/– mice showed a clear reduction in their inflammatory response toward LPS. The reduced gene induction after LPS treatment was not a result of differences in the LPS receptor complex, as no differences in cell-surface expression of TLR4 and CD14 were observed between wild-type and S100A9–/– cells. Moreover, no differences in the expression or motility of intracellular components of the TLR4 signaling cascade such as MyD88 or NF-{kappa}B factors p50 and p65 were observed. The reduced LPS-dependent up-regulation of proinflammatory proteins such as TNF-{alpha} in S100A9–/– cells correlated with a reduced binding of the NF-{kappa}B factors p50 and p65 to the TNF-{alpha} promoter and thus, a regulation at the transcriptional level. S100A8/S100A9 was secreted readily by bone marrow cells and monocytes following LPS stimulation, which pointed toward an extracellular, autocrine function of S100A8/S100A9 during LPS activation. In agreement with this hypothesis, addition of extracellular S100A8/S100A9 compensated for the impaired response of S100A9–/– cells to LPS. Interestingly, S100A8 alone stimulated TNF-{alpha} RNA expression and protein secretion and had an additive effect on LPS-induced TNF-{alpha} secretion. S100A8/S100A9, however, had only additive effects on TNF-{alpha} secretion in the presence of LPS. This indicates that active extracellular function of these proteins is somehow regulated by S100A8/S100A9 complex formation and that activation of the S100A8/S100A9 complex needs an additional, so far unknown, trigger during inflammatory processes. Further analysis revealed that LPS and S100A8 induced identical signal transduction pathways, including translocation of MyD88 from the cytosol to the TLR4 receptor complex and activation of IRAK1, as well as ERK, p38 MAPK, and PKC. Moreover, phagocytes obtained from mice with a nonfunctional TLR4 receptor showed no response to S100A8. Direct binding of S100A8 to a TLR4-MD2 complex was confirmed by surface plasmon resonance studies with a KD of 1.1–2.5 x 10–8 M. S100A8 stimulated NF-{kappa}B-dependent gene expression in embryonic kidney cells transfected with all components of the TLR4 signaling complex. Most important, S100A9–/– mice showed significantly enhanced survival rates and reduced TNF-{alpha} serum levels during LPS-induced septic shock. Addition of extracellular S100A8/S100A9 restored susceptibility in S100A9–/– mice. Similar results were observed in Escherichia coli-induced abdominal sepsis. These in vivo results clearly exclude a contribution from a potential LPS contamination to the observed effects. In addition, multiple controls regarding potential LPS contaminations were performed in all in vitro experiments according to recently published suggestions [76 ].

In conclusion, these data clearly indicate that S100A8/S100A9 acts as an endogenous TLR4 ligand involved in amplification of LPS effects on phagocytes (Fig. 1 ) upstream of TNF-{alpha}. Although TNF-{alpha} is critical for LPS toxicity [77 ], blockade of TNF-{alpha} had a harmful rather than protective effect in human sepsis [78 , 79 ]. Moreover, in a small study, S100A8/S100A9 levels were demonstrated to decrease in surviving patients during recovery from sepsis, and nonsurvivors were characterized by high S100A8/S100A9 serum levels [40 ]. Thus, blockade of soluble S100A8/S100A9 or blockade of S100A8/S100A9 secretion during sepsis could represent a promising new therapeutic option.


Figure 1
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  		Figure 1. S100A8/S100A9 is an endogenous TLR4 ligand. (A) S100A8/S100A9 binds to TLR4 on phagocytes, independent from CD14. Binding of S100A8/S100A9 to TLR4 triggers an autokrine-positive feedback loop, which results in an amplification of endotoxin-induced up-regulation of cytokine, chemokine, and ROS. (B) S100A8/S100A9 mediated signal transduction via TLR4. S100A8 binds to TLR4 and activates distinct signal transduction cascades. As the native S100A8/S100A9 complex in serum of healthy people is inactive, S100A8 has to be expressed and/or released independently from the complex under specific inflammatory conditions, or the S100A8/S100A9 complex has to be activated by a so-far unknown trigger. The asterisks indicate those components of the TLR-mediated signal transduction cascades, which have been demonstrated to be activated by S100A8 binding.


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S100A8/S100A9 AND AUTOIMMUNITY
 
In infection, S100A8/S100A9 amplifies the host response to pathogen-derived factors such as LPS. Moreover, it has been demonstrated recently that S100A8/S100A9 also amplifies inflammatory reactions triggered by endogenous factors. It was long known that the S100A8/S100A9 serum as well as synovial levels are up-regulated in patients suffering from arthritis and autoimmune disease (for review, see refs. [6 , 31 , 80 ]). Indeed, S100A8 and S100A9 have been identified initially in early infiltrating phagocytes in RA [81 ]. S100A8/S100A9-expressing phagocytes were identified at sites of maximal cartilage destruction in RA [82 ]. Moreover, there is evidence for local release of S100A8/S100A9 in the synovia, as the levels measured in synovial fluids are more than 20-fold greater than those measured in parallel in serum from individual patients [33 , 36 , 83 , 84 ]. Serum levels of S100A8/S100A9 were found to correlate better with disease activity and joint destruction in RA and psoriatic arthritis than classical markers of inflammation such as erythrocyte sedimentation rate and CRP [33 , 34 , 84 ].

In SOJIA, S100A8/S100A9 concentrations, in contrast to CRP, distinguish SOJIA from infections with high specificity [37 ]. SOJIA is associated with increased activation of the inflammasome, resulting in extensively elevated IL-1β serum levels. In vivo, blockade of IL-1β resulted in a decrease of S100A8A/S100A9 serum levels, and in turn, S100A8/S100A9 stimulated IL-1β expression in monocytes. Thus, S100A8/S100A9 and IL-1β represent a novel positive-feedback mechanism in SOJIA.

As a result of these clinical data, a contribution of S100A8/S100A9 to the pathogenesis of different types of arthritis can be assumed. This has been verified recently using S100A9–/– mice [73 , 85 ]. van Lent et al. [85 ] demonstrated strong and early up-regulation of S100A8 and S100A9 in experimental antigen-induced arthritis. Moreover, S100A9–/– mice, which lack functional S100A8/S100A9 complexes, display significantly reduced joint swelling, metastable nuclear isomer of technetium-99 uptake, and leukocyte infiltration during antigen-induced arthritis. The antigen-dependent T cell response, however, was not impaired. S100A8/S100A9 deficiency was demonstrated to be protective against proteoglycan depletion, MMP-mediated cartilage destruction, and chondrocyte death. S100A8 induced MMP expression in murine macrophages, and a single injection of S100A8 into knee joints resulted in up-regulation of cytokines and MMPs as well as in proteoglycan depletion 1 day after the injection. These results clearly indicate that macrophage-derived S100A8/S100A9 amplifies the inflammatory response in antigen-induced arthritis and also acts as endogenous DAMP in the absence of infection or pathogenic agents.

Further analysis revealed that S100A8 was actively involved in MMP-mediated chondrocyte activation and subsequent cartilage destruction [73 ]. S100A8/S100A9 was expressed by chondrocytes in experimental murine arthritis and human RA. Stimulation of a murine chondrocyte cell line by proinflammatory cytokines resulted in increased expression of S100A8 and S100A9 mRNA and protein. In addition, a potential autocrine-feedback loop for S100A8/S100A9 was identified, as S100A8 stimulated IL-6 secretion from chondrocytes. Moreover, in contrast to previous findings in a cell-free in vitro system, where S100A8/S100A9 inhibited MMP activity as a result of zinc chelation [86 ], S100A8 stimulation in vivo resulted in increased MMP expression and activation, as revealed by up-regulation of MMP-induced neoepitopes on chondrocytes and in anatomically intact cartilage in experimental models of arthritis. S100A8 stimulation resulted in NF-{kappa}B activation in chondrocytes. However, cell-surface expression of TLR4, the dominant receptor for S100A8 in macrophages, was low in chondrocytes. Antibodies against RAGE did not affect S100A8-induced MMP activation, and an antibody against carboxylated glycans showed a substantial inhibition of MMP activation. In conclusion, S100A8 acts as an autocrine positive-feedback activator in chondrocytes, which further confirms its critical role, not only as disease marker but also in the pathology of arthritis.


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S100A8/S100A9 AND CANCER
 
S100A8/S100A9 expression is increased in patients with various tumors. Thus, besides its effects in inflammation, S100A8/S100A9 may also affect tumor biology [87 ]. An effect of S100A8/S100A9 on tumor cells seems possible, as tumor cells express TLR4, the endogenous receptor of S100A8/S100A9 [88 ].

In vitro, S100A8/S100A9 was reported to induce apoptosis in diverse human and murine tumor cell lines [89 90 91 ]. Therefore, an anti-tumor activity was proposed for S100A8/S100A9. However, a demonstration of this proposed anti-tumor activity in vivo is lacking. Moreover, a tumor-promoting activity of S100A8/S100A9 was demonstrated recently in vitro: S100A8/S100A9 binds to colonic tumor cells in a carboxylated glycan-dependent manner, activated NF-{kappa}B, and induced cell proliferation [75 ]. As S100A8/S100A9-positive cells infiltrate colon tumors, and anti-carboxylated glycan antibodies reduced chronic inflammation and tumorigenesis significantly, it was concluded that colitis-associated carcinogenesis in vivo was augmented by S100A8/S100A9 [75 ].

Most important, recent data indicate that in mice, S100A8/S100A9 promoted tumor growth as well as metastatic tumor spread by mechanisms independent from its potential effect on tumor cells. The group of Gabrilovich [92 ] reported reduced growth of lymphomas and sarcomas in S100A9–/– mice and linked these findings to a reduced generation of MDSCs, which are immature myeloid cells that have been demonstrated to arise in man and mice suffering from diverse tumors. They inhibit the adaptive, CD8+ T cell-driven anti-tumor immune responses efficiently [93 , 94 ]. The authors observed up-regulation of S100A8 and S100A9 expression in splenocytes from tumor-bearing wild-type mice, which was restricted to a Gr-1+ cell population. As tumors are known to induce differentiation of Gr-1+ MDSCs, their accumulation was analyzed in tumor-bearing S100A9–/– mice. No accumulation of MDSCs could be observed in these mice. Moreover, the induction of MDSCs from hematopoietic stem cells by tumor-conditioned medium was inhibited severely in S100A9–/– mice. In wild-type mice, tumor cell-conditioned medium induced MDSC differentiation and simultaneously inhibited differentiation of dendritic cells and macrophages. The authors provide evidence that overexpression of S100A8/S100A9 in progenitor cells affects myeloid differentiation by increasing production of ROS. However, genome-wide expression screening in S100A9–/– mice revealed multiple alterations in gene expression and differentiation of myeloid cells [10 ]; thus, more complex effects of S100A8/S100A9 on MDSC differentiation are certainly possible, and soluble factors secreted from tumor cells induce overexpression of S100A8/S100A9, resulting in increased generation of MDSCs. These MDSCs can inhibit anti-tumor responses by CD8+ T cells and thus promote tumor growth.

Sinha et al. [95 ] independently analyzed the importance of S100A8/S100A9 for tumor biology and MDSC function. In agreement with the results from Gabrilovich’s group [92 ], MDSCs were found to express S100A8/S100A9. However, Sinha et al. [95 ] presented evidence for an action of extracellular S100A8/S100A9 on MDSCs. They demonstrated carboxylated N-glycan-mediated binding of S100A8/S100A9 to MDSCs and activation of NF-{kappa}B. Moreover, MDSCs secreted S100A8/S100A9, indicating a potential autocrine effect. Importantly, treatment of mice with an antibody blocking carboxylated N-glycans and thus, S100A8/S100A9-binding sites on MDSCs reduced MDSC recruitment and accumulation as well as S100A8/S100A9 serum levels. Thus, the relative contribution of extracellular versus intracellular effects of S100A8/S100A9 for MDSC-ediated immunosuppression has to be determined in further studies.

Moreover, S100A8/S100A9 expression is not only induced in hematopoietic precursors from tumor-earing mice but also in lung phagocytes. There, S100A8/S100A9 seems to act as an extracellular signal involved in guiding tumor cell entry and metastasis formation in this organ [15 , 96 ]. Soluble factors released from tumors such as TNF-{alpha}, TGF-β, and VEGF seem to be responsible for induction of S100A8 and S100A9 in the lung. S100A8/S100A9 secreted by lung macrophages consecutively induces expression of chemotactic factors, which recruit inflammatory phagocytes. This inflammatory setting facilitates immigration and metastasis formation by tumor cells.

Recently, Hiratsuka et al. [96 ] identified SAA3 as an important downstream target of S100A8/S100A9 expression in lungs of tumor-bearing mice. S100A8 increased expression of SAA3 in lungs in vitro, and neutralizing antibodies directed against S100A8 and S100A9 reduced tumor-induced expression of SAA3 in vivo. SAA3 induced chemotaxis of tumor cells and phagocytes and acted as a positive-feedback regulator for further chemoattractant secretion. SAA3 was identified as an endogenous ligand of TLR4, and blocking of SAA3 and TLR4 in vivo reduced metastasis formation. The authors concluded that S100A8/S100A9, SAA3, and TLR4 represent a paracrine positive-feedback cascade, which is critical for inducing an inflammatory response in pre-metastatic lungs and thus, renders this organ susceptible for tumor cell immigration and metastasis formation.

Whether these processes are independent from the described effects of S100A8/S100A9 on MDSCs has to be established in further studies. Especially, the type of phagocytes described by Hiratsuka et al. [15 ], which express S100A8/S100A9 in pre-metastatic lungs, has to be characterized further. Hiratsuka et al. [15 ] identified these cells as phagocytes as a result of their expression of macrophage antigen-1 (consisting of CD11b and CD18 subunits); thus, it cannot be excluded that these cells are CD11b, Gr1+ MDSC, and more research is needed to define the role of S100A8/S100A9 in tumor biology. The possible interactions between tumors and S100A8/S100A9 are depicted in Figure 2 .


Figure 2
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  		Figure 2. S100A8/S100A9 and cancer. S100A8/S100A9 has direct and indirect effects on tumor progression. S100A8/S100A9 sustains inflammation and is involved in colitis-associated carcinogenesis. Soluble factors derived from tumors increase S100A8/S100A9 expression in hematopoietic stem cells, which results in increased differentiation of MDSC. Some tumors, which preferentially develop distant metastases in the lung, have been shown to secrete factors that increase S100A8/S100A9 expression in lungs. There, S100A8/S100A9, SAA3, and TLR4 represent a paracrine positive-feedback cascade, which is critical for inducing an inflammatory response in pre-metastatic lungs and thus, renders this organ susceptible for tumor cell immigration and metastasis formation.


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OTHER EXTRACELLULAR FUNCTIONS OF S100A8/S100A9
 
Murine S100A8/S100A9 was described as a chemotactic factor for phagocytes [97 , 98 ]. A chemotactic activity of S100A8/S100A9 on leukocytes and tumor cells was also implicated in the mestatasis-promoting function of S100A8/S100A9 in tumor biology [15 , 96 ]. However, these effects only occurred at low concentrations of S100A8/S100A9, which are 100- to 10,000-fold lower compared with those levels measured in serum of healthy controls or of patients suffering from inflammatory diseases. Thus, the relevance of these findings in vivo is in our opinion highly questionable.

However, S100A8/S100A9 is clearly implicated in stimulating inflammatory cell immigration in vivo as a result of its action on endothelial cells and phagocytes, which results in secretion of chemokines and priming of phagocytes and endothelial cells for leukocyte extravasation.

In a murine model of streptococcal pneumonia, it was demonstrated recently that inhibition of S100A8/S100A9 blocks phagocyte migration to the alveoli but not to lung tissue [99 ]. S100A8/S100A9-neutralizing antibodies did not decrease chemokine levels, indicating that other mechanisms are responsible for inhibition of phagocyte recruitment into the airspace.

S100A8 expression was shown to be induced by glucocorticoids, and IL-10 in macrophages in vitro and numbers of S100A8-positive macrophages were elevated significantly in RA patients treated with high-dose steroids [100 , 101 ]. Thus, an anti-inflammatory function of S100A8 as a scavenger of oxidants [102 ] was suggested. Recently, an inhibitory effect of S-nitrosylated S100A8 on mast cell activation was demonstrated [103 ]. However, all data obtained from the S100A9–/– mouse model clearly confirmed a proinflammatory function of S100A8/S100A9, which is in accordance with the expression pattern of these molecules in many human inflammatory diseases.

The designation calprotectin for the S100A8/S100A9 complex was derived from its ability to inhibit bacterial as well as fungal growth in vitro [104 ]. This was proposed to be a result of the ability of S100A8/S100A9 to chelate the nutrient Zn2+ [105 106 107 ]. Recently, a moderate increase in susceptibility of S100A9–/– mice toward infection with Staphylococcus aureus was demonstrated [108 ]. In wild-type mice, S100A8/S100A9 was expressed in neutrophils within bacterial abscesses. S100A8/S100A9 inhibited bacterial growth in vitro as a result of chelation of the bacterial nutrients Mn2+. In vivo, higher levels of Mn2+ were found within abscesses of S100A9–/– compared with wild-type mice, indicating a contribution of chelation of metal nutrients to the observed, increased susceptibility toward bacterial infection. No general deficiency in phagocyte effector functions is observed in S100A9–/– mice [10 , 32 ]. However, the role of S100A8/S100A9 as amplifier of the inflammatory response via binding to TLR4 or other ligands expressed on phagocytes or endothelial cells was not analyzed in this study. Thus, the relative contribution of these antimicrobial effects versus activities of S100A8/S100A9 as DAMP currently remains an open question.


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S100A8/S100A9 AS EPIDERMAL DANGER SIGNAL
 
In normal epidermis, S100A8 and S100A9 are expressed at low levels. Both proteins, however, are highly overexpressed in psoriasis and other inflammatory skin diseases such as lichen planus and lupus erythematosus [109 , 110 ]. Recently, S100A8/S100A9 was established as a general danger signature of activated keratinocytes, as its expression can be induced in response to a wide variety of skin stresses including tape stripping, exposure to detergent, UV exposure, or cytokine stimulation (e.g., IL-1{alpha}, IL-22) [44 , 45 , 111 112 113 ]. As S100A8/S100A9 in turn induces proinflammatory cytokine and chemokine expression as well as proliferation of normal human keratinocytes [114 ], it could represent an important part of a positive-feedback mechanism in initiation and amplification of inflammatory skin disease. Moreover, it could be critically involved in epidermal hyperproliferation as seen in human psoriasis and animal models of psoriasis but also in wound healing [23 , 45 , 46 , 115 , 116 ]. In addition, treatment of mouse skin with tumor promoters increased S100A8/S100A9 expression [74 , 117 ], indicating that S100A8/S100A9 plays a role in inflammation-induced carcinogenesis.

Interestingly, in psoriasis, up-regulation of epidermal S100A8/S100A9 expression seems to be responsible for increased S100A8/S100A9 serum levels, which correlated with disease activity [46 ]. In line with these findings, epidermal overexpression of S100A8/S100A9 during the typical skin rash was an early sign in patients suffering from systemic onset of juvenile idiopathic arthritis [38 , 118 ] and correlated with the highly increased serum levels. In addition, the epidermis may be a source of serum S100A8/S100A9 levels in SLE [110 , 119 ]. Interestingly, skin symptoms are frequently the first clinical sign of SLE [120 ]. Moreover, in mice, modulation of epidermal gene expression by deletion of the transcription factor c-jun resulted not only in epidermal overexpression of S100A8/S100A9 and hyperproliferative skin disease but also in arthritis, which is also frequently present in human psoriatic patients [115 ]. These findings indicate that S100A8/S100A9 released from epidermal cells may act as a systemic danger signal and thus, be involved in the initiation of systemic autoimmune or inflammatory disorders.


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CONCLUSION
 
Like most DAMPs, S100A8/S100A9 exhibits a kind of double life: Within granulocytes and monocytes, which express both proteins under steady-state conditions, they play a profound role in cell homeostasis, especially in regulation of the cytoskeleton. After secretion to the extracellular compartment by a nonclassical pathway, S100A8/S100A9 becomes a crucial danger signal during inflammatory processes in infection, autoimmunity, and cancer. Moreover, cell types that do not express S100A8/S100A9 under homeostatic conditions such as epithelial cells or chondrocytes are able to up-regulate S100A8/S100A9 expression in response to stress, PAMPs, or other danger signals [15 , 46 , 47 , 73 ]. The association of inflammation and S100A8/S100A9 was discovered more than 20 years ago, but the molecular mechanisms involved in danger signaling by extracellular S100A8/S100A9 are only beginning to emerge recently. Especially, no distinct receptor for S100A8/S100A9 had been characterized. Thus, the identification of TLR4 as the dominating receptor for S100A8/S100A9 in human monocytes and most probably, also on other cell types represents a hallmark for our understanding of S100A8/S100A9 as DAMP [10 ]. Importantly, S100A8/S100A9 is not only involved in amplifying the inflammatory response in infections but has also been identified recently as an important regulator of inflammation in experimental arthritis [73 , 85 ] as well as in cancer development and tumor spreading [15 , 92 , 95 , 96 ]. S100A8/S100A9 amplifies inflammatory responses via autocrine and paracrine mechanisms involving phagocytes, endothelial cells, chondrocytes, and tumor cells. As a net result, extravasation of leukocytes into inflamed tissues is increased, and infiltrating phagocytes are activated directly by S100A8/S100A9- and by S100A8/S100A9-induced cytokines. Thus, S100A8/S100A9 plays a pivotal role during local amplification of inflammation. Moreover, some reports indicate that S100A8/S100A9 released from inflamed tissues to the systemic circulation may also trigger susceptibility of distinct organ systems toward autoimmunity and inflammatory disorders [28 , 46 , 115 , 118 ]. Thus, a detailed analysis of the mechanisms limiting S100A8/S100A9 expression and inducing resolution of inflammation should improve our knowledge about the development of chronic inflammatory disorders and result in the discovery of new therapeutic targets to treat or even better, prevent these burdening diseases.


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ACKNOWLEDGMENTS
 
This work was supported by grants from the Interdisciplinary Center for Clinical Research to T. V., J. R., D. F., J. M. E., and C. S. (Ro2/012/06, Sun2/019/07, Fö2/005/06, and Vo2/014/09) and by grants from the German Research Foundation to T. V., D. F., and C. S. (VO 882/2-1, FO 354/2-2, SU 195/3-1) and the German Ministry for Research (BMBF/DLR Fkz: 01Kl07100).


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FOOTNOTES
 
Abbreviations: CRP=C-reactive protein, DAMP=damage-associated molecular pattern, EF hand=helix–loop–helix domain, FGF=fibroblast growth factor, HMEC=human microvascular endothelial cell, IRAK=IL-1R-associated kinase, MD2=myeloid differentiation protein 2, MDSC=myeloid-derived suppressor cell, MMP=matrix metalloproteinase, MRP=myeloid-related protein, PAMP=pathogen-associated molecular pattern, PKC=protein kinase C, PRR=pattern recognition receptor, RA=rheumathoid arthritis, RAGE=receptor for advanced glycation end products, ROS=reactive oxygen species, SAA3=serum amyloid A3, SLE=systemic lupus erythematosus, SOJIA=systemic onset of juvenile idiopathic arthritis, VEGF=vascular endothelial growth factor

Received October 20, 2008; revised March 26, 2009; accepted March 26, 2009.


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