S100 Proteins in Psoriasis and Other Autoimmune Diseases: Comparison
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Very well-known AMP-family members are S100 proteins that constitute the largest, multigenic, and calcium-binding protein family in vertebrates. Over 20 types of these proteins have been identified, of which 13 are expressed in the normal or diseased human epidermis. The name of the S100 proteins is due to their biochemical characteristics, namely, they are 100% soluble in saturated ammonium sulfate at neutral pH. S100 proteins are small, acidic proteins with a molecular weight of 9–13 kDa. They are produced as monomers, but exist in cells as anti-parallel homo- and heterodimers, in which monomers are held together by non-covalent bonds and are oriented by a two-fold axis of rotation. Dimers can further associate to form higher-order multimers [187]. Each S100 monomer consists of two helix–loop–helix structural motifs that are Ca2+-binding domains termed EF-hands. 

  • S100 proteins
  • koebnerisin
  • antimicrobial peptides and proteins
  • immune-mediated inflammatory diseases
  • biomarkers

1. S100 Proteins as Biomarkers and Therapeutic Targets

Changes occurring during the disease compared to normal tissues at the gene or protein level are now considered an appropriate way to identify disease markers that may be correlated with disease pathogenesis or response to treatment. Many S100 proteins have been identified in body fluids, which can be used as biomarkers for the detection of a specific disease, where an increased level of their expression indicates a pathological state [195,196,197,198][1][2][3][4]. Due to the wide range of functions of the S100 proteins, various diseases such as chronic inflammatory diseases are associated with altered levels of specific S100 proteins. The specific S100 protein may be induced under pathological conditions in a cell type that does not express it under normal physiological conditions. For this reason, S100 proteins are being discussed as potential biomarkers for many diseases. Members of the S100 family of proteins intensively studied in the course of psoriasis include S100A4, S100A7, S100A8, S100A9, S100A12, S100B and Koebnerisin (S100A15), indicating their involvement in the pathogenesis of the disease [1,16,17,18,19,22,24,194,199,200][5][6][7][8][9][10][11][12][13][14]. However, some studies show no correlation between mRNA expression and plasma levels of the protein, which makes it difficult to assess the possibility of using the S100 protein as a biomarker of psoriasis. For example, the results of the research by Duvetorp et al. [18][8] showed a significant reduction in the S100A8/A9 skin protein level after NB-UVB treatment, while the serum concentration remained unchanged, thus questioning the function as a psoriasis biomarker. Moreover, conflicting data are found in the literature on the expression of S100A7 in the serum of psoriasis patients under different treatment regimens [1,201,202,203][5][15][16][17]. The reason for these discrepancies remains unclear, but it has been suggested to be due to different ELISA tests used by the research groups. Both the conflicting results and the still poor understanding of the role of S100 proteins in the development of autoimmune diseases and their potential therapeutic significance provide strong arguments for further research focusing on this issue. The potential role of some S100 proteins as biomarkers and therapeutic targets in selected autoimmune diseases and comorbidities is discussed below.
Blood levels of S100A12 are elevated in patients with diabetes [204][18], coronary artery disease [205][19], and psoriasis [1][5], and this protein is also used as a biomarker to detect other inflammatory diseases such as systemic juvenile idiopathic arthritis [206][20] or acute infectious exacerbations common in cystic fibrosis [196][2]. Moreover, the intense local expression of S100A12 is indicative of a pro-inflammatory function during airway inflammation in cystic fibrosis, suggesting that this protein may serve as a new target for therapies. The anti-inflammatory effect of methotrexate in patients with inflammatory arthritis was associated with a decrease in serum levels of S100A12, suggesting that S100A12 alone may be a therapeutic target in this disease as well [205,207][19][21].
S100A4 has proven to be a valuable biological marker and therapeutic target for many types of cancer. Determination of S100A4 levels in tumor tissues or body fluids can predict the prognosis and metastasis of cancer patients in the early stages. Several molecular targeting strategies have been developed [208][22] for its protein as inhibition of S100A4 expression may reduce metastasis in vivo. It has been reported [209][23] that S100A4 is a novel biomarker of glioblastoma stem cells, the increased expression of which contributes to the emergence of a metastatic phenotype. Chow et al. [209][23] also established that S100A4 is a central node in a molecular network that controls stemness and epithelial-mesenchymal transition in glioblastoma, suggesting S100A4 as a novel candidate therapeutic target. Increased urine levels of S100A4 have been reported in patients with a complex inflammatory autoimmune disease, childhood-onset systemic lupus erythematosus, indicating S100A4 role as a marker for lupus nephritis activity [197][3]. However, there is still a great clinical need to develop new therapeutic agents that act to modulate the expression and activity of S100A4 [15][24].
TNF-α, IL-17, and IL-22-induced S100A7 have been found to be abundantly expressed in psoriatic lesions or serum from psoriatic patients as well as in atopic dermatitis skin lesions [2,19,24,210,211][9][11][25][26][27]. Moreover, an increased level of S100A7 has been found in the cerebrospinal fluid and brain of Alzheimer’s patients as a function of clinical dementia [212][28]. ThisIt studywas also confirmed the hypothesis that the promotion of S100A7 expression in the brain can selectively promote α-secretase activity in patients with Alzheimer’s disease (AD), preventing the production of amyloidogenic peptides. S100A7 might be developed as a novel surrogate biomarker of therapeutic efficacy for the treatment of AD. Dysregulation of S100A7 is also associated with the occurrence of many malignancies, including, for example, ovarian cancer [213][29], cervical cancer [213][29], and prostate cancer [214][30]. A new therapeutic strategy is the use of neutralizing monoclonal antibodies against S100A7 in the treatment of cancer [215][31].
In clinical practice, tests are available that allow the determination of the S100B protein, the presence of which in the serum is a marker of melanoma, useful in the diagnosis, prognosis, and treatment monitoring [216,217,218][32][33][34]. Histochemically, S100B is detected in 100% of neuroblastoma and neurofibroma cells, in 50% of malignant peripheral nerve sheath tumors, and in other neoplastic cells. In histopathology, S100B is an established immunohistochemical marker of choice for malignant melanoma [219][35]. However, the main clinical importance of S100B in the diagnosis of melanoma is the determination of its concentration in the blood serum [220,221][36][37]. S100B is a clinical marker of melanoma progression and metastasis useful in serological monitoring of systemic therapy. The survival time in patients with a lower baseline serum concentration of S100B is significantly longer than in patients with a higher concentration, regardless of the stage of cancer. In the diagnosis of melanoma, the determination of serum S100B is a marker of greater diagnostic utility than classic markers such as lactate dehydrogenase or alkaline phosphatase.
Increased concentration of S100A8/A9 (calprotectin) in serum has been observed in patients with coronary artery disease [222][38] and may act as a serum biomarker of obesity in patients without type 2 diabetes [223][39]. Furthermore, calprotectin has also been shown to be a useful biomarker of disease activity in the treatment of inflammatory bowel diseases (IBDs) such as Crohn’s disease [224][40]. Importantly, the detection of S100A8/A9 in feces can be used to differentiate IBD from irritable bowel syndrome [225][41]. S100A8/A9 proteins are involved in various types of cancer. Their increased expression indicates a key role in inflammation-related cancers [226][42], including chronic lymphocytic leukemia [227][43], breast cancer [228][44], laryngeal cancer [229][45], hepatocellular carcinoma [230][46], and bladder cancer [231][47]. S100A8/A9 proteins represent promising biomarkers for assessing the risk potential of various types of cancer in molecular pathology. A higher baseline serum calprotectin level may predict that patients with psoriasis vulgaris will experience improvement after treatment with methotrexate [17][7]. Moreover, a higher concentration of S100A8/A9 was associated with the risk of relapse of the disease after discontinuation of methotrexate. S100A8/A9 may, therefore, be a promising predictive marker of psoriasis severity.
Other members of the S100 family of proteins may prove to be useful biomarkers for future applications, and therapies targeting the S100 protein may prove to be useful possibilities under certain clinical conditions. However, their pathophysiological implications still require further clarification before they can be successfully investigated in a clinical context. Currently, proposed therapeutic strategies targeting S100 proteins include, among others, inhibition of S100 protein expression, targeted degradation, and antibody-mediated binding of S100 proteins [184,232,233][48][49][50]. The most common therapeutic approaches include inhibition of S100 protein expression using microRNA-, small interfering RNA- or short hairpin RNA-based knockdown of S100 proteins using neutralizing antibodies or using specific small-molecule inhibitors. While some inhibitors appear to be effective by inhibiting S100 gene transcription, others inhibit S100 protein activity by disrupting the interaction between S100 proteins and their targets [233][50]. Target binding cleavages of S100 proteins that are exposed to calcium ion binding can easily bind small molecules [184][48]. Consequently, considerable success has been achieved in identifying small molecules that block S100–target protein interactions. Several anti-allergy drugs, such as cromolyn, amlexanox, tranilast, and olopatadine, have been reported to bind multiple S100 proteins [234,235,236][51][52][53]. Other anti-allergy drugs have been found to bind to the S100A12 protein, blocking RAGE signaling and subsequent NF-κB activation [237][54]. Other examples of small-molecule S100 inhibitors include covalent inhibitors that modify Cys residues in helix IV of the S100B and S100A4 proteins. Despite the proximity of these cysteines to the C-terminal EF-hand, their modification does not affect Ca2+ binding but disrupts Zn2+ mediated conformational rearrangements in S100B and target binding to both S100A4 and S100B [238,239][55][56]. Selectivity of this modification is an issue. A covalent inhibitor of S100A4 and S100B, 2,3-bis [2-hydroxyethylsulfanyl]-1,4-naphthoquinone, also inhibits the activity of many protein tyrosine phosphatases by modifying the Cys active site [240,241][57][58]. Small-molecule inhibitors that inhibit S100 gene transcription have also been found. Calcimycin, a calcium ionophore, and sulindac sulfide (sulindac), a non-steroidal anti-inflammatory drug, inhibit the expression of β-catenin, leading to reduced levels of target genes, including S100A4 [242,243,244][59][60][61]. Treatment of mice with these inhibitors resulted in reduced tumor growth, reduced invasion, and fewer colorectal cancer metastases at least in part due to lower levels of S100A4 [242,244][59][61]. In addition to disrupting the interaction between S100 proteins and their targets, targeting covalent modifications such as S-nitrosylation, S-glutathionylation and phosphorylation may be a promising strategy because these modifications affect the function of S100 proteins [233][50]. Therefore, targeting these modifications may provide an indirect way to modulate S100 structure or function, thereby affecting pathophysiology and disease progression [15,184][24][48]. Function-blocking antibodies targeting receptors and ligands have been widely used as therapeutic agents to treat many pathologies, including immune disorders [245,246,247,248][62][63][64][65]. Given the extensive evidence indicating that extracellular S100 proteins mediate the inflammatory response in many pathological conditions primarily through cell receptor signaling, the use of antibodies that block S100 function may therefore be an effective therapeutic strategy for treating these conditions. Limiting S100A8/A9 activity with small-molecule inhibitors or neutralizing antibodies has been observed to alleviate pathological conditions in mouse models. Some quinoline-3-carboxamides, compounds currently under investigation for the treatment of human autoimmune and inflammatory diseases, interact with S100A9 and the S100A8/A9 complex, thereby blocking their interaction with TLR4 or RAGE and inhibiting TNF-α release in vivo [249][66]. Blockade of S100A8/A9 has also recently been observed to reduce inflammatory processes in mouse models of arthritis [250][67]. Importantly, it has been suggested that S100A8 would be a good target against obesity-induced chronic inflammation [251][68]. In addition, a monoclonal antibody targeting extracellular S100A7 was designed [215][31]. It could be shown that this antibody against S100A7, named 6F5, blocks the S100A7/RAGE interaction, thereby inhibiting S100A7-induced MMP9 activity, leading to reduced tumor growth, cell migration and angiogenesis in a xenograft cancer model. Several miRNAs were introduced to target S100 protein expression [233][50]. Among them, two miRNAs, namely miR-187-3p [252][69] and miR-149-3p [253][70], were found to downregulate S100A4 expression. S100A7 expression could be downregulated by miR-26b-5p, leading to reduced proliferation, migration and invasion of intrahepatic cholangiocarcinoma in vitro [254][71]. Similar effects were observed for miR-24, a miRNA targeting S100A8, which inhibited the proliferation and invasion of laryngeal cancer cells [255][72]. Elucidating the mechanisms of action of S100 proteins in the pathophysiology of human diseases may lead to the development and application of new, more effective therapeutic approaches. ThisIt reviewwas describesd that several promising approaches to using S100 proteins as valuable tools for treating autoimmune disorders. However, much more research is needed to broadly define S100 proteins as reliable biomarkers and to identify and further optimize safe and effective S100 therapies. A better understanding of the role of S100 proteins will greatly benefit new clinical applications.

2. Koebnerisin (S100A15)

Gene duplication and variation during primate evolution led to an increase in member number and thereby diversity within the S100 protein family [256][73]. In 2003, during the analysis of differential gene expression in psoriasis, a new member of the S100 family was discovered, namely S100A15 [20][74]. S100A15 is a 101 amino acid protein, in which amino acids 13–48 probably form the N-terminal EF-hand motif, while amino acids 50–85 are part of the canonical C-terminal EF-hand (Figure 41) [257][75]. It is worth noting that S100A15 has a basic isoelectric point unusual for S100 proteins, which is probably due to the loss of acidic and the introduction of basic amino acids in the acidic C-terminus [20][74]. Human S100A15 is overexpressed in “koebnerized” psoriatic skin and, thus, the proposed name is koebnerisin [19,21][9][76]. Koebnerisin is encoded within the EDC (chromosome 1q21), which has been identified as one of the psoriasis candidate loci (PSORS4) that has been genetically linked to disturbed differentiation and susceptibility to skin inflammation [22][10]. Unlike other members of S100, the koebnerisin gene reveals an unusual genomic organization [20,22,24,256][10][11][73][74]. While most S100 proteins encode a single transcript, two alternatively spliced mRNA-isoforms of koebnerisin have been found: S100A15-S (short isoform) and S100A15-L (long isoform). Both S100A15 transcripts share the same coding region but differ in 3′- and 5′-untranslated region (UTR) length (0.5 kb vs. 4.4 kb) and composition [19,20,194][9][12][74].
Molecules 27 06640 g004 550
Figure 41. Structures of S100A15 protein: (a) predicted amino acid sequence of the human S100A15 (the red color marks those amino acids that bind Zn2+, while the green color marks the amino acids that bind Ca2+); (b) structure of human S100A15 coordinating Zn2+ and Ca2+—image from the RCSB PDB (rcsb.org) of PDB ID 4AQI [187][77].
The S100A15 gene is organized into three exons with exon 1 being not translated and exons 2 and 3 containing the coding region, and two introns with all exon/intron boundaries following the GT-AG rule [20][74]. Exon 1 occurs only in the S100A15-L transcript, while the S100A15-S transcript starts with an additional sequence enlarging the 5′-UTR of exon 2, which is not a part of the S100A15-L transcript. Both splice variants are differentially expressed in healthy, non-lesional, and lesional psoriatic skin, which indicates regulation by alternate promoters [194][12]. In the skin, the expression of the S100A15-L mRNA-isoform is more pronounced than the S100A15-S. In healthy skin, koebnerisin is expressed by both differentiated (granular and cornified layer) and non-differentiated (basal layer) keratinocytes of the epidermis [19,194,256][9][12][73]. Additionally, S100A15 can be found in Langerhans cells, melanocytes, and dendritic cells [186][78]. Within the pilosebaceous unit, koebnerisin is localized both in the internal and external root sheath. In the dermis, S100A15 can be also detected in endothelial tissue, the basal layer of the sebaceous gland as well as in smooth muscle cells. Koebnerisin is secreted into the extracellular space, where it acts as an antimicrobial peptides and proteins (AMPs) against Escherichia coli, Staphylococcus aureus, and Pseudomonas Aeroginosa [258][79]. In the model of psoriasis, the inflammation susceptibility of keratinocytes is mediated by the upregulation of S100A15 [22][10]. When secreted to the extracellular medium, koebnerisin drives the production of some proinflammatory cytokines (autocrine loop) and attracts immunocytes (paracrine effect). Then, it establishes a subtle inflammation-prone environment.
An external stimulus such as trauma leads to Koebnerization and the further proinflammatory cascade is amplified (inflammation priming). During inflammation, levels of S100A15 significantly increase and this protein is now distributed to the whole epidermis, which might be due to the altered calcium gradient along with disturbed maturation in the psoriatic skin [194][12]. In addition to the regulation of koebnerisin by disturbed calcium-induced epidermal differentiation, also proinflammatory environment contributes to the expression of S100A15 in human skin. Psoriasis is characterized by increased epidermal proliferation, abnormal keratinocytes differentiation, and infiltrating inflammatory cells [192][80]. In inflamed skin, the levels of immune cells such as neutrophils, lymphocytes, granulocytes, and macrophages increase significantly. The infiltrating cells express high amounts of proinflammatory cytokines, such as IFNγ, IL-12, IL-23, and IL-17 [23][81]. During chronic inflammation, koebnerisin is mainly induced by Th1-, Th17- and Th22-derived cytokines, such as IL-17A, TNF-α, IL-22, IL-1β, and IFN-γ that create a characteristic psoriatic proinflammatory milieu [19,23,192,194][9][12][80][81]. Data [258][79] suggest that IL-17A is the principal inducer of S100A15 in human keratinocytes. The cytokine environment with the increase in S100A15 expression catalyzes the vicious cycle of inflammation. Koebnerisin primes keratinocytes to enhance the production and secretion of subsequent immunotropic cytokines such as IL-6, IL-8, and TNF-α, which are crucial in the development of psoriatic lesions [23,192][80][81]. Inflammation priming and amplification require S100A15 binding to the as-yet-unknown pertussis toxin-sensitive Gi-protein-coupled receptor (GiPCR) [19,22,23][9][10][81]. Koebnerisin potentiates inflammation by acting directly as a chemoattractant for leukocyte subsets, especially granulocytes and monocytes, further increasing the number of inflammatory cells infiltrating the skin and amplifying a pro-inflammatory feedback loop in psoriasis. While koebnerisin induces a proinflammatory response by itself, its proinflammatory activity is potentiated when it acts with highly homologous S100A7 (psoriasin) which indicates that they contribute to inflammation independently, but synergistically [200,256][14][73]. Inflammatory products of psoriatic skin are then released into the systemic circulation reflecting the severity and extent of psoriatic lesions [260][82]. As a result, it potentiates systemic inflammation and contributes to the development of psoriatic comorbidities [24,260][11][82]. Moreover, Batycka-Baran et al. [24][11] confirmed the expression of S100A15 by human leukocytes, where the S100A15 gene was also transcribed into two alternate splice variants. In contrast to the skin, S100A15-S was a more prominent isoform in all investigated leukocyte subsets, but both transcripts were predominantly expressed in lymphocytes and monocytes. Then, koebnerisin acted as a danger molecule (‘alarmin’) by priming these immune cells to produce proinflammatory cytokines. Compared to the healthy control, there were increased levels of koebnerisin transcripts in peripheral blood mononuclear cells of psoriatic patients. Therefore, circulating leukocytes may contribute to the increased level of S100A15 both in skin lesions and in the serum of patients with psoriasis, which indicates that extracellular koebnerisin, may be considered a biomarker associated with this disease. This is also confirmed by the fact that the use of narrow-band UVB therapy significantly reduces the amount of koebnerisin expressed in the leukocytes of patients with psoriasis as well as calcipotriol contributes to a decreased level of S100A15 in psoriatic skin, which gives this protein a valuable role as a marker of therapeutic response in psoriasis [24,192][11][80]. Researches [24,260,261][11][82][83] show a broader spectrum of S100A15 activity as a mediator of inflammation, not only in the skin but also beyond, which may have systemic consequences in the form of comorbidities in psoriasis, such as atherosclerosis and obesity. Awad et al. [260][82] evaluated the role of serum koebnerisin as a potential link between psoriasis and atherosclerosis. The results of these studies confirmed the usefulness of S100A15 as a marker of subclinical atherosclerosis in patients with psoriasis. Thus, targeting the S100A15-mediated loop may be an excellent approach in the treatment of psoriasis and comorbidities in the future.

3. The Function of Koebnerisin in Other Immune-Mediated Inflammatory Diseases

In the last decade, some researchers have addressed other disease fields of SA10015. Batycka-Baran et al. [262][84] showed a relevant role of koebnerisin as a protein that might exert a proinflammatory effect in rosacea. The level of S100A15 was upregulated within the epidermis and dermis in rosacea lesional skin compared with the healthy control, suggesting its role in the regulation of keratinocytes’ functions. It is well known that koebnerisin can prime leukocytes and keratinocytes to enhance the production of proinflammatory cytokines such as TNF-α and IL-1β with a significant role in rosacea. The study showed in turn that TNF-α enhanced the expression of S100A15 in keratinocytes and fibroblasts, which might create a vicious circular cycle of inflammation. Moreover, it was found that koebnerisin may exert additional proangiogenic effects by stimulating keratinocytes and fibroblasts to increase the production of the potent proangiogenic mediator vascular endothelial growth factor (VEGF). In addition, S100A15 can trigger fibroblasts to increase the expression of matrix metalloproteinase 9 (MMP-9), which has a damaging effect on skin components, thereby stimulating innate immune responses and inflammatory processes. In conclusion, koebnerisin may be a new player in the pathogenesis of rosacea. Balancing the activity of certain antimicrobial proteins may be a target for future therapeutic interventions in rosacea.
Another study by Batycka-Baran et al. [263][85] showed increased expression of koebnerisin in lesional and perilesional skin in patients suffering from hidradenitis suppurativa compared to a healthy control. Similar results were also obtained by Zouboulis et al. [264][86], who detected a strong overexpression of S100A15 in hidradenitis suppurativa skin, especially in stratum granulosum. Real-time PCR and immunofluorescence analysis with specific monoclonal antibodies were used to examine the expression of S100A15 in the skin [263][85]. Patients with hidradenitis suppurativa had not received any local or systemic anti-inflammatory therapy for at least 8 weeks before the study. Disease severity was graded according to Hurley classification (stage I-4, stage II-5, and stage III-5). Two punch biopsies were taken from each volunteer, one of the inflammatory lesions and the other 2 cm from the affected skin. S100A15 was found to be overexpressed in the epidermal suprabasal and basal compartments of the perilesional and lesional skin in patients with hidradenitis suppurativa. It has been suggested that the overexpression of koebnerisin in the perilesional hidradenitis suppurativa skin may indicate its role in the early phase of disease pathogenesis, as well as contribute to the hidradenitis suppurativa susceptibility. Skin biopsies from clinically uninvolved, perilesional hidradenitis suppurativa skin show perifollicular and perivascular inflammatory infiltrates. Koebnerisin triggers keratinocytes to increase the production of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-8. Elevated levels of these early induced proinflammatory mediators were found in hidradenitis suppurativa skin. Furthermore, S100A15 is involved in the pathogenesis of hidradenitis suppurativa as a chemoattractant for neutrophils and monocytes/macrophages. Therefore, S100A15 can promote the development of inflammatory processes in the skin. The same study showed an increase in S100A8 levels in lesional skin compared to skin in the lesion area, but, in contrast to the S100A15, there was no significant difference in S100A8 expression in the perilesional hidradenitis suppurativa skin compared to healthy skin. Nevertheless, S100A8 may enhance inflammation in patients with hidradenitis suppurativa by stimulating keratinocytes to increase the production of proinflammatory mediators and attracting other immune cells. In a later study, Batycka-Baran et al. [265][87] investigated S100A15 and S100A4 serum levels in patients suffering from hidradenitis suppurativa and their association with disease severity, C-reactive protein (CRP) serum levels, and other demographic and clinical data. The S100A4 protein showed a statistically significant increase in concentration in plasma samples of hidradenitis suppurativa subjects compared to controls. Significant differences in S100A4 levels were also observed between different Hurley stages with the highest concentration in patients in Hurley II stage. The S100A4 serum concentration in the patients in Hurley stage II and III was significantly elevated as compared to those of the healthy controls and subjects with hidradenitis suppurativa in Hurley stage I, but there was no significant difference in the S100A4 serum levels between the patients in Hurley stages II and III. They also found no significant correlations between serum S100A4 concentration and CRP levels, body mass index (BMI), smoking, and other demographic and clinical data. In contrast to S100A4 protein, the study showed no significant differences (p > 0.05) in serum S100A15 levels between whole individuals with hidradenitis suppurativa (156.1 ± 133.8 pg/mL) and healthy volunteers (153.9 ± 134.8 pg/mL). However, an association has been shown between disease severity (estimated based on Hurley staging system) and koebnerisin serum levels in patients with hidradenitis suppurativa (50.8 ± 30.9 pg/mL, 151.5 ± 115.7 pg/mL, 317.1 ± 101.0 pg/mL in Hurley stage I, II and III, respectively). There were statistically significant differences in concentration of koebnerisin in serum between the Hurley stages (p < 0.0001), as well as between S100A15 serum levels in patients in Hurley stage III compared with controls (p = 0.0013). Moreover, a positive correlation was found between the serum concentration of S100A15 and CRP in patients with hidradenitis suppurativa, which may suggest an association between the disease and increased cardiovascular risk resulting from chronic systemic inflammation. However, as with S100A4, no relationship was found between S100A15 levels and BMI, smoking, or other demographic or clinical data. TheIt authorwas proposed that S100A4 and S100A15 as novel serum biomarkers for monitoring hidradenitis suppurativa progression and suggested their role in the pathogenesis of the disease by promoting inflammation and fibrosis.
The genes of the S100 protein family are dysregulated during carcinogenesis, and today, some S100 members have been established as markers of tumor progression [266,267,268,269][88][89][90][91]. Psoriasin and koebnerisin form the highly homologous S100 subfamily and are regulated throughout tumor progression in epithelial cancers [266][88]. Despite their 93% of sequence homology, S100A7 and S100A15 differ in expression, function, and mechanism of action and are, therefore, exemplary of the diversity within the S100 family. The corresponding single ortholog mS100a7a15 in mice shares the expression and functional properties of the two human proteins. Psoriasin and koebnerisin are co-expressed in mature epithelial cells of mammary lobules and ducts, as well as in differentiated epithelial skin layers, but are difficult to distinguish. Their expression is induced along with markers of late differentiation in calcium-differentiated keratinocytes. In epithelial carcinomas, S100A7 and possibly S100A15 are often elevated at early tumor stages, such as in pre-invasive carcinomas. Within tumor tissue, both proteins are expressed in well-differentiated tumor cells and show an expression pattern like that observed in normal mature epithelial cells. S100A7 is downregulated in adjacent invasive cancer tissues; however, once the expression persists, the nuclear translocation of psoriasin is related to a poor clinical prognosis. Within the nucleus, psoriasin is assumed to bind and trigger c-jun activation domain-binding protein-1 (Jab1). Nuclear translocation of psoriasin and Jab1-dependent effects leads to increased cell survival and proliferation. In invasive breast carcinomas, S100A7 and S100A15 are co-regulated and related to estrogen/progesterone receptor-negative and more aggressive tumors. Koebnerisin nuclear translocation has not been studied, but because of mutations within the Jab1 binding site, it may not be able to bind to Jab1 compared to psoriasin. A similar suggestion was made by Wolf et al. [270][92]. Oncogenic effects may also be mediated by the release of the S100 protein into the extracellular space where it interacts with cell surface receptors, for example, RAGE, which is responsible for maintaining inflammation and promoting carcinogenesis [266][88]. Increased serum levels of S100A7 were considered a potential marker of epithelial cancer progression. Extracellular psoriasin can bind to RAGE and thus activate NF-κB, which controls the transactivation of several genes involved in immune responses as well as cell proliferation and apoptosis. In inflammation-related carcinogenesis, NF-κB is a key player in helping precancerous and malignant cells escape from tumor surveillance mechanisms by activating anti-apoptotic genes. Koebnerisin is unable to induce RAGE signaling but interacts with an as-yet-unknown Gi protein-coupled receptor. S100A7 and S100A15 are two proteins that are exploited by the tumor not only to adapt cellular signaling pathways that regulate the survival of the tumor but also to modify the surrounding microenvironment to escape tumor surveillance, as well as to promote cancer cell migration. In a breast cancer model, the mouse S100a7a15 ortholog induced matrix metalloproteinases (MMP-2) and angiogenic factors, such as VEGF resulting in enhancing tumor malignancy. Moreover, mS100a7a15 can recruit leukocytes and tumor-associated macrophages (TAM) via RAGE/Stat3 signaling and thus promote tumor progression and metastasis. The human orthologs are chemoattractants and able to recruit myeloid cells, such as monocytes, but their participation in the evasion of tumor surveillance by attracting TAM has not been investigated yet. Compared to S100A7, koebnerisin is produced additionally by tumor surrounding non-epithelial cells such as dendritic cells, epithelial-derived myoepithelial cells around acini, and surrounding blood vessels. Psoriasin and koebnerisin can mediate the immune response by stimulating the secretion of TNF-α, IL-1, IL-6 and IL-8. In immune cells, these pro-inflammatory cytokines lead to the NF-κB-dependent secretion of growth factors that enhance the proliferation and survival of cancer cells. In addition, the attracted macrophages, mast cells, and neutrophils may also enhance non-specific immune responses that may lead to enhanced tumor growth. Despite the few reports about the opposing effects of psoriasin and koebnerisin in multifunctional pathways and in mechanisms that are known to affect epithelial carcinogenesis, still, little is known about the recently discovered koebnerisin. Several functions that are referred to psoriasin might actually be due to koebnerisin signaling. Their different properties are very important reasons for the need to discriminate psoriasin and koebnerisin in epithelial homeostasis, inflammation, and carcinogenesis.
The results obtained by Yung-Che et al. [269][91] provide evidence that koebnerisin enhances metastasis in lung adenocarcinoma in vivo and in vitro by hypomethylation of DNA in the gene promoter region and downstream mediators focused on CTNNB1. Researchers found that hypomethylation of the S100A15 promoter at three CpG sites and its increased expression was associated with both a higher metastatic potential and poorer outcomes in patients with pulmonary adenocarcinoma. This phenomenon has been verified in lung adenocarcinoma cell lines with high and low metastatic properties. As the accumulation of koebnerisin in the nucleus has been demonstrated by immunochemical staining in patients with distant metastatic pulmonary adenocarcinoma, it is speculated that its nuclear translocation from under the cell membrane is the first step to exerting its further oncogenic effects. More research is needed to elucidate the relationship between S100A15 promoter DNA hypomethylation and its nuclear translocation. The study did not reveal a clinical relationship with S100A15 in the other two pathological types of lung cancer, namely squamous cell carcinoma and small-cell carcinoma. This could be for several reasons. First, the interaction between the epidermal growth factor receptor and the S100A family can promote angiogenesis and metastasis in various cancers, while the proportion of EGFR mutations is relatively small in these two types of lung cancers. Second, some members of the S100A family contribute to the progression of squamous cell carcinoma, while others maintain the differential status of the epithelium and contribute to a less invasive type of cancer. Although nuclear S100A15 has been relatively strongly expressed in squamous cell carcinoma, its biological function in this type of lung cancer remains to be established. Third, little expression of the S100A family is found in various small-cell neoplasms. Koebnerisin may not play a key role in small-cell lung cancer. On the other hand, downstream S100A15 signaling, which may be important for cancer cell survival, remains largely unknown. Next-generation sequencing data identified 518 differentially expressed genes upregulated by S100A15 and 1378 differentially expressed genes downregulated by S100A15, the former having been mapped to 46 seed genes of the subnetwork. Among them, CTNNB1, ZEB1, CDC42, HSP90AA1, BST2, PCNA, and E2F1 have been shown to promote lung cancer progression, while SAMHD1, HRAS, and NQO1 serve as tumor suppressor genes. Thus, S100A15 promotes tumor progression in adenocarcinoma of the lung. S100A15 can exert its oncogenic function, initiated by DNA hypomethylation in the promoter region of the gene and mediated by downstream genes focused on CTNNB1. Both increased expression of S100A15 and hypomethylation of the promoter DNA of its gene can serve as biomarkers predicting high metastatic potential and poor outcomes in adenocarcinoma patients. Further research into the functions of S100A15 and its epigenetic regulation could provide a potential treatment strategy for lung cancer.

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