Upregulation of cathepsin S in psoriatic keratinocytes

Schönefuß, Alexander; Wendt, Wiebke; Schattling, Benjamin; Schulten, R.; Hoffmann, Klaus H.; Stüecker, Markus; Tigges, Christian; Lübbert, Hermann; Stichel, Christine C.

doi:10.1111/j.1600-0625.2009.00990.x

Cited by 60 publications

(42 citation statements)

References 77 publications

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“…Interestingly, a previous study using cathepsin S staining of biopsies has suggested that cathepsin S may be up-regulated in psoriatic lesions (30). To consolidate and quantify these findings, cathepsin S protein levels were analyzed in tape-strip samples acquired from the skin of psoriasis patients and healthy controls.…”

Section: Resultsmentioning

confidence: 99%

Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ

Ainscough

Macleod

McGonagle

et al. 2017

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

129

121

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The proinflammatory cytokine IL-36γ is highly expressed in epithelial cells and is a pivotal mediator of epithelial inflammation. In particular, IL-36γ is strongly associated with the inflammatory skin disease psoriasis. As with other IL-1 cytokines, IL-36γ is expressed as an inactive precursor and must be processed by specific proteases to become bioactive. Our aim therefore was to identify protease/s capable of IL-36γ activation and explore the importance of this activation in psoriasis. Using a keratinocyte-based activity assay in conjunction with small-molecule inhibitors and siRNA gene silencing, cathepsin S was identified as the major IL-36γ-activating protease expressed by epithelial cells. Interestingly, cathepsin S activity was strongly up-regulated in samples extracted from psoriasis patients relative to healthy controls. In addition, IL-36γ-Ser18, identified as the main product of cathepsin S-dependent IL-36γ cleavage, induced psoriasiform changes in human skin-equivalent models. Together, these data provide important mechanistic insights into the activation of IL-36γ and highlight that cathepsin S-mediated activation of IL-36γ may be important in the development of numerous IL-36γ-driven pathologies, in addition to psoriasis.T he interleukin (IL)-1 family cytokines are fundamental regulators of the innate immune system and orchestrate multiple inflammatory responses (1, 2). IL-1 cytokines are produced rapidly following infection or injury and are capable of potently inducing a range of beneficial proinflammatory processes, including additional cytokine expression, antigen-presenting cell migration, and leukocyte activation and infiltration (3-5). The aberrant expression and regulation of IL-1 cytokines is associated with a broad range of immuopathologies, ranging from autoinflammatory to autoimmune disorders (6-8). Therefore, a greater insight into the regulation and function of IL-1 cytokines is not only of academic interest but also of significant therapeutic importance.IL-36α, IL-36β, and IL-36γ are agonistic cytokines and the most recently discovered of the IL-1 family (9). Interestingly, there is growing evidence to suggest that these cytokines are important for the development of several inflammatory disorders, including psoriasis (10). In psoriatic lesions, the IL-36 cytokines have been shown to be among the most specific and highly up-regulated mRNAs relative to other inflammatory skin diseases and healthy controls (11-13). Moreover, hypomorphic mutations in the IL-36 receptor antagonist (IL-36Ra) cause the severe and potentially lethal subtype of psoriasis called pustular psoriasis in a number of cohorts (14, 15). Mouse models further support these observations, showing that IL-36 overexpression in keratinocytes results in a transient inflammatory skin condition resembling psoriasis (16). In addition, IL-36 receptor-deficient mice have been found to be resistant to Imiquimod-induced psoriasiform dermatitis (17). Interestingly, recent studies have also demonstrated a role for the IL-36 recept...

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Section: Resultsmentioning

confidence: 99%

Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ

Ainscough

Macleod

McGonagle

et al. 2017

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

129

121

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“…Cathepsin S is associated with inflammatory processes and chronic itch conditions. The expression of cathepsin S is upregulated in psoriatic keratinocytes [33]. Mice carrying a transgene expressing cathepsin S spontaneously develop atopic dermatitis [34].…”

Section: Discussionmentioning

confidence: 99%

Mrgprs activation is required for chronic itch conditions in mice

Zhu

Hanson

Liu

et al. 2017

Itch

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Introduction Chronic itch has been drawing much attention due to its clinical significance and the complexity of its mechanisms. To facilitate the development of anti-itch strategies, it is necessary to investigate the key players in itch sensation under chronic itch conditions. Several members of the Mrgpr family were identified as itch receptors that detect cutaneous pruritogens in primary sensory neurons. However, the role of Mrgprs in chronic itch conditions has not been well described. Methods Scratching behaviors of WT and Mrgpr-clusterΔ−/− mice were examined in dry skin model and contact dermatitis model to examine the role of Mrgpr genes in mediating chronic itch sensation. Scratching behaviors of the mice were also examined in allergic itch model. Real-time PCR were performed to examine the expression level of MrgprA3 and MrgprC11 under naïve and dry skin conditions. The MrgprA3+ itch-sensing fibers were labeled by tdTomato fluorescence in Mrgpra3GFP-Cre; ROSA26tdTomato mice, and the morphology and density of those fibers in the epidermis were analyzed under dry skin condition. Results We showed that deleting a cluster of Mrgpr genes in mice reduced scratching behavior severely under two chronic itch conditions, namely dry skin and contact dermatitis, and the allergic itch condition. Moreover, the gene expressions of itch receptors MrgprA3 and MrgprC11 in dorsal root ganglia (DRG) were upregulated significantly under dry skin condition. Consistently, the percentage of MrgprA3+ itch-sensing neurons was increased as well. We also observed hyperinnervation of MrgprA3+ itch-sensing fibers in the epidermis of the skin under dry skin condition. Discussion We demonstrate that Mrgprs play important roles in mediating chronic itch and allergic itch. These findings enrich our knowledge of itch mechanism and may lead to the development of novel therapeutic approach to combat itch.

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“…Increased cathepsin K expression in psoriatic lesion and the skin of K5.Stat3C mice Previous studies demonstrated increased levels of CTSs B, D, L, and S in psoriasis (19,20). We analyzed the expressions of Ctsk, Ctsb, Ctsl, and Ctss in human psoriasis (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cathepsin K Is Involved in Development of Psoriasis-like Skin Lesions through TLR-Dependent Th17 Activation

Hirai

Kanda

Satô

et al. 2013

The Journal of Immunology

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Cathepsins (CTSs) are lysosomal cysteine proteases that play an important role in the turnover of intracellular proteins and extracellular proteins, such as the degradation of extracellular matrices and the processing of antigenic proteins. A CTS inhibitor, NC-2300, not only suppresses bone erosion by inhibition of cathepsin K (CTSK), but also ameliorates paw swelling at inflamed joints in adjuvant-induced arthritis in rats. It has been demonstrated that the amelioration of joint inflammation by NC-2300 is mediated by the downregulation of cytokine expression in dendritic cells, which are essential for Th17 activation. In this work, we studied the role for CTSs in the pathogenesis of psoriasis-like lesion in K5.Stat3C mice, a mouse model of psoriasis, in which Th17 contributes to lesion development similar to psoriasis. Psoriatic lesions expressed increased levels of Ctsk and Ctss mRNA compared with uninvolved skin and normal control skin. Similarly, the epidermis and dermis in K5.Stat3C mice demonstrated increased CTSK activities, which were sensitive to NC-2300. Topical treatment with NC-2300 significantly ameliorated 12-O-tetradecanoylphorbol-13-acetate–induced psoriasis-like lesions in K5.Stat3C mice, and downregulated the expression of IL-12, IL-23, and Th17 cytokines. In vitro experiments revealed that TLR7 activation of bone marrow–derived myeloid dendritic cells led to increase in IL-23 at mRNA and protein levels, which were downregulated by NC-2300. These results suggest that CTSK plays a role in development of psoriatic lesions through TLR7-dependent Th17 polarization.

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Upregulation of cathepsin S in psoriatic keratinocytes

Cited by 60 publications

References 77 publications

Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ

Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36γ

Mrgprs activation is required for chronic itch conditions in mice

Cathepsin K Is Involved in Development of Psoriasis-like Skin Lesions through TLR-Dependent Th17 Activation

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