ReviewPhagocyte-derived S100 proteins in autoinflammation: Putative role in pathogenesis and usefulness as biomarkers
Highlights
► S100A8/A9 and S100A12 are released from activated phagocytes. ► S100 proteins are released via alternative secretory pathways. ► Dysregulated alternative secretion may be involved in autoinflammation. ► S100A8/A9 and S100A12 are valid biomarkers for autoinflammatory diseases.
Introduction
The S100 protein family represents the largest subgroup within the Ca2 +-binding EF-hand superfamily. Their name has derived from the observation that the first identified S100 proteins were obtained from the soluble bovine brain fraction upon fractionation with saturated (100%) ammonium sulfate [1]. Phylogenetically, these proteins appear to be rather young, as they are only present in vertebrates [2]. Most of the S100-coding genes cluster on human chromosome 1q21. This clustered organization gave rise to the systematic nomenclature of S100 proteins: polypeptides encoded by genes located within the cluster on chromosome 1 were assigned as S100A proteins with numbers A1–A16, reflecting the position of the gene in the cluster [3], [4]. The remaining S100 genes are located on chromosomes 21q22 (S100B), Xp22 (S100G), 4p16 (S100P), and 5q14 (S100Z).
All S100 proteins share key structural motifs although their sequence homology does not exceed 65% [5]. The monomeric forms with molecular weights between 10 and 13 kDa consist of two EF-hand helix–loop–helix structures connected by a flexible linker. The C-terminal EF-hand contains the classical Ca2 +-binding motif whereas the N-terminal EF-hand exhibits an extended loop structure which is specific for S100 proteins (“pseudo EF hand”), resulting in reduced Ca2 + affinity. Thus, a monomer can bind two Ca2 + ions, each with different affinities. Intracellularly this may be of functional relevance in a second messenger context, as the pseudo-EF-hand can only be Ca2 +-loaded once respective levels are high. For S100 proteins with reported extracellular function as S100A8, A9 and A12 it is of note that physiological Ca2 + levels outside the cells are sufficient to ensure Ca2 +-saturation of the proteins [6].
Besides Ca2 +-binding through EF-hand motifs S100 proteins are reported to bind Zn2 + with high affinity. However, also other divalent metal ions such as Cu2 + or Mn2 + can be bound [7]. In S100A8, A9 and A12, Zn2 + is bound exclusively via the side chains of His, Glu and Asp residues [8], [9], [10]. A hallmark of S100 proteins is the formation of multimeric complexes. As examples, S100A8 and A9 form heterocomplexes, while S100A12 forms homocomplexes. Metal-ion binding by S100 proteins has pronounced impact on protein conformation and consequently oligomerization and thus function [11], [12], [13], [14], [15].
Although the genes of S100 proteins are located in a cluster, there is no evidence that their expression is synchronized either in a cell-specific or developmental manner. Instead, many studies suggest that in a given cell type, a certain S100 protein may be expressed abundantly while the one encoded by a neighboring gene reveals low or no expression. Each S100 protein has a very specific expression pattern [16], [17], [18]. Further, expression of an individual protein may be completely different between cell lines derived from related sources. As attempts to study the role of cell-specific transcription factors in S100 expression has failed so far, alternative explanations are searched in studies on epigenic regulation of S100 expression [19].
Constitutive expression of the three calgranulin genes S100A8 (calgranulin A, also referred to as myeloid-related protein, MRP8), S100A9 (calgranulin B, MRP14) and S100A12 (calgranulin C) is largely restricted to phagocytic myeloid cells, in particular granulocytes and monocytes. S100A8 and S100A9 are the most abundant proteins in neutrophils, comprising approximately 40% of the cytosolic protein content and considered to majorly contribute to calcium-binding capacity in these cells [20], [21]. S100A8/A9 heterocomplexes are also referred to as ‘calprotectin’ in the literature [22]. S100A12 is specifically expressed in granulocytes, accounting for approx. 5% of cytosolic protein content [23]. Calgranulins are not expressed in tissue macrophages while low levels can be found in monocytes. As there is no expression detectable in B or T cells, this points towards a role of these proteins in innate rather than adaptive immune mechanisms [24].
Section snippets
Intracellular functions
So far, a number of intracellular calgranulin functions have been proposed. For S100A8/A9 it was originally believed that they act as calcium buffers, calcium sensors and/or intracellular differentiation factors for phagocytes. For S100A12 a similar involvement in buffering intra- versus extracellular Zn2 + has been proposed [10]. However, in phagocytes of S100A9−/− mice only minor differences in intracellular calcium signaling could be observed in comparison to wild-type cells [25]. Moreover,
Cryopyrin-Associated Periodic Syndromes
Mutations in the NLRP3 (CIAS1/NALP3/PYPAF1) gene locus 1q44, encoding for cryopyrin/NALP3 protein, cause diseases with overlapping phenotypes. Cryopyrin-Associated Periodic Syndromes (CAPS) comprise a group of rare autoinflammatory diseases, which include the Familial Cold Autoinflammatory Syndrome (FCAS), the Muckle–Wells Syndrome (MWS), and the Neonatal-Onset Multiorgan Inflammatory Disease (NOMID). Cryopyrin regulates the production of proinflammatory cytokines interleukin (IL)-1β and IL-18,
Use as biomarkers
In recent years, patient outcomes in autoinflammatory diseases have improved dramatically due to a deeper understanding of the pathophysiology and the availability of effective therapies. However, chronic inflammatory diseases including autoinflammatory syndromes are heterogeneous disorders with variable disease progression and treatment response. While some patients respond to a single therapy, others require more intensive treatment strategies. Better biomarkers for this heterogeneity are
S100 proteins as potential therapeutic targets
A molecule of the group of quinoline-3-carboxamides has been identified to inhibit S100 activity by binding to S100 proteins S100A8/A9. This approach has been shown to be effective in animal models of inflammation [103]. Furthermore chinolones have been shown to be promising as a therapy for autoimmunity in the human system [104]. In the light of these recent data it is conceivable that S100 proteins may also represent promising targets for treating autoinflammatory diseases. While this may be
Conclusion and outlook
In summary, phagocyte-derived S100 proteins derived from cells of myeloid origin are promising new markers of autoinflammation. S100A8/A9 and S100A12 concentrations correlate to disease activity, both during local and systemic inflammation. In monogenic syndromes involving inflammasome mutations, the S100 proteins may further amplify inflammation, e.g. in concert with IL1 or IL18 in CAPS. A dysregulation of alternative secretory pathways may be involved in pathogenesis and lead to
Conflict of interest statement
None of the authors has any potential financial conflict of interest related to this manuscript.
Acknowledgments
This work has been supported by grants from the German Research Foundation (DFG Fo 354/3-1 and SFB1009) and the German Ministry for Education and Science (BMBF 01GM08100).
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