Elevated serum levels of calcium-binding S100 proteins A8 and A9 reflect disease activity and abnormal differentiation of keratinocytes in psoriasis

Benoit, Sandrine; Toksoy, Atiye; Ahlmann, Martina; Schmidt, Marc; Sunderkötter, Cord; Foell, Dirk; Pasparakis, Manolis; Roth, Johannes; Goebeler, Matthias

doi:10.1111/j.1365-2133.2006.07198.x

Cited by 138 publications

(115 citation statements)

References 23 publications

(19 reference statements)

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“…These discrepancies may well be associated with inherent differences in the type of antigen used, and the duration of the in vitro assays, and future studies will no doubt need to further address this. It is also plausible that the S100A8/A9 pathway described in this study is also involved in other inflammatory diseases, such as inflammatory bowel disease (43), RA (16), psoriasis (44), and cystic fibrosis (45), all diseases where both S100A8/A9 proteins and IL-17 have been implicated in disease progression and pathology (21).…”

Section: Discussionmentioning

confidence: 81%

S100A8/A9 Proteins Mediate Neutrophilic Inflammation and Lung Pathology during Tuberculosis

Gopal¹,

Monin²,

Torres-García³

et al. 2013

Am J Respir Crit Care Med

199

197

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Rationale: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. Objectives: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. Methods: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. Measurements and Main Results: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/ A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. Conclusions: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.Keywords: inflammation; tuberculosis; neutrophil; S100A8/A9 proteins; granuloma A hallmark of pulmonary tuberculosis (TB) in humans and experimentally infected animals is the formation of granulomas. However, the immune factors that drive the formation of the protective granuloma during latent TB, and the factors that drive the inflammatory granulomas formed during active TB, are not well defined. What This Study Adds to the FieldThis study demonstrates the dominant presence of neutrophils producing S100 proteins within the inflammatory lung granulomas of patients with active TB. This study also describes a link between S100A8/A9 protein induction, neutrophil accumulation, and pathology associated with the inflammatory granuloma formed during TB, because S100A8/A9 deficiency in mice reverses exacerbated inflammation during TB. In addition, this study demonstrates the potential use of S100A8/A9 proteins along with neutrophilattracting chemokines in serum as surrogate biomarkers to assess inflammation and disease severity in TB in humans.

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Section: Discussionmentioning

confidence: 81%

S100A8/A9 Proteins Mediate Neutrophilic Inflammation and Lung Pathology during Tuberculosis

Gopal¹,

Monin²,

Torres-García³

et al. 2013

Am J Respir Crit Care Med

199

197

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“…The antimicrobial peptides S100A8, S100A9, and Lcn2 are reported targets of IL-17 cytokines in keratinocytes and are highly expressed in psoriatic lesions (33,34). S100A8, S100A9, and Lcn2 were induced significantly in IMQ-treated dorsal skin of WT but not CIKS-KO mice (Fig.…”

Section: Resultsmentioning

confidence: 94%

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

Wang

Pisitkun

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

127

114

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Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory cells. The mechanisms underlying psoriasis in humans and in mouse models are poorly understood, although evidence strongly points to crucial contributions of IL-17 cytokines, which signal via the obligatory adaptor CIKS/Act1. Here we identify critical roles of CIKS/Act1-mediated signaling in imiquimod-induced psoriatic inflammation, a mouse model that shares features with the human disease. We found that IL-17 cytokines/CIKS-mediated signaling into keratinocytes is essential for neutrophilic microabscess formation and contributes to hyperproliferation and markedly attenuated differentiation of keratinocytes, at least in part via direct effects. In contrast, IL-17 cytokines/CIKS-mediated signaling into nonkeratinocytes, particularly into dermal fibroblasts, promotes cellular infiltration and, importantly, leads to enhanced the accumulation of IL-17-producing γδT cells in skin, comprising a positive feed-forward mechanism. Thus, CIKS-mediated signaling is central in the development of both dermal and epidermal hallmarks of psoriasis, inducing distinct pathologies via target cell-specific effects. CIKS-mediated signaling represents a potential therapeutic target in psoriasis.

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“…Ca 2ϩ homeostasis of the epidermis, and potentially calgranulins, is involved in the formation of the skin barrier, which is known to be impaired in psoriasis, and in cytokine activation of lymphocytes. In addition, the calgranulin genes are overexpressed in the psoriatic epidermis with respect to both mRNA and protein concentrations, and the calprotectin concentration in serum has been correlated with disease activity (14 ). All of these findings point to a potential, although so far unproved, role for calgranulins in psoriasis pathogenesis.…”

Section: Discussionmentioning

confidence: 92%

“…(A), Thb4 concentrations in plasma of psoriasis patients and healthy controls as assessed by an ELISA specific for the N terminus of Thb4 (amino acid residues [1][2][3][4][5][6][7][8][9][10][11][12][13][14] and by an ELISA developed in-house that is specific for full-length Thb4 (residues 1-43). (B), Relative concentrations of calgranulin A and calgranulin B (spectral counts) and concentrations of calprotectin (ELISA measurements).…”

Section: Discussionmentioning

confidence: 99%

“…The proteins with altered concentrations belonged to the extracellular, Ca 2ϩ -binding, lipoprotein, complement, protease/protease inhibitor, and cytoskeletal protein groups (Table 1), all of which have previously been associated with certain autoimmune disorders and psoriasis in particular (14 -20 ). Only a few of the individual proteins, however, including calgranulins A and B, galectin 3, and galectin 3-binding protein, have been linked to psoriasis or are known to be altered in psoriatic plasma or serum (14,21 ). We also observed increased concentrations of the acute-phase reactants C-reactive protein, fibrinogen, ␣ 1 -antitrypsin, and ␣ 2 -macroglobulin, but the increases were below the established cutoff value of 2 for the ratio of the median concentrations of the 2 groups and therefore are not reported in Table 1.…”

Section: Proteomic and Peptidomic Analysismentioning

confidence: 99%

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Increased Plasma Concentrations of Cytoskeletal and Ca2+-Binding Proteins and Their Peptides in Psoriasis Patients

et al. 2008

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Elevated serum levels of calcium-binding S100 proteins A8 and A9 reflect disease activity and abnormal differentiation of keratinocytes in psoriasis

Cited by 138 publications

References 23 publications

S100A8/A9 Proteins Mediate Neutrophilic Inflammation and Lung Pathology during Tuberculosis

S100A8/A9 Proteins Mediate Neutrophilic Inflammation and Lung Pathology during Tuberculosis

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

Increased Plasma Concentrations of Cytoskeletal and Ca2+-Binding Proteins and Their Peptides in Psoriasis Patients

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