IL-36γ (IL-1F9) Is a Biomarker for Psoriasis Skin Lesions

D’Erme, Angelo Massimiliano; Wilsmann‐Theis, Dagmar; Wagenpfeil, Julia; Hölzel, Michael; Ferring-Schmitt, Sandra; Sternberg, Sonja; Wittmann, Miriam; Peters, Bettina; Bosio, Andreas; Bieber, Thomas; Wenzel, Joerg

doi:10.1038/jid.2014.532

Cited by 223 publications

(223 citation statements)

References 37 publications

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“…IL-36 cytokines are overexpressed in affected skin of patients with inflammatory skin diseases, including atopic dermatitis and psoriasis (25)(26)(27)(28). The functional importance of this upregulation is supported by several recent findings: IL-36g mediates the alarmin function of the antimicrobial peptide LL37, and it functions as an alarmin that signals pathogen infections (20,29); injection of IL-36a promotes myeloid cell infiltration and their activation in the skin (30); tg mice overexpressing IL-36a in keratinocytes develop a psoriasis-like phenotype (31); the psoriasiform dermatitis that develops in mice after treatment with imiquimod depends on an IL-36-mediated cross-talk between dendritic cells and keratinocytes (32); and IL-36RA deficiency causes generalized pustular psoriasis in humans (33).…”

Section: Discussionmentioning

confidence: 99%

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

Kurinna

Muzumdar

Köhler

et al. 2016

The Journal of Immunology

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The Nrf2 transcription factor is well known for its cytoprotective functions through regulation of genes involved in the detoxification of reactive oxygen species or toxic compounds. Therefore, activation of Nrf2 is a promising strategy for the protection of tissues from various types of insults and for cancer prevention. However, recent studies revealed a proinflammatory activity of activated Nrf2 and a stimulating effect on epithelial cell proliferation, but the underlying mechanisms of action and the responsible target genes are largely unknown. Using a combination of gene expression profiling, chromatin immunoprecipitation, and targeted proteomics via selected reaction monitoring, we show that the gene encoding the proinflammatory cytokine IL-36γ is a novel direct target of Nrf2 in keratinocytes and hepatocytes in vitro and in vivo. As a consequence, upregulation of IL-36γ expression occurred upon genetic or pharmacological activation of Nrf2 in the epidermis and in the normal and regenerating liver. Functional in vitro studies demonstrate that IL-36γ directly stimulates proliferation of keratinocytes. In particular, it induces expression of keratinocyte mitogens in fibroblasts, suggesting that the Nrf2–IL-36γ axis promotes keratinocyte proliferation through a double paracrine loop. These results provide mechanistic insight into Nrf2 action in the control of inflammation and cell proliferation through regulation of a proinflammatory cytokine with a key function in various inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

Kurinna

Muzumdar

Köhler

et al. 2016

The Journal of Immunology

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“…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)(12)(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).…”

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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.

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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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“…Moreover, these factors may contribute to the recruitment of immune cells, including neutrophils, which can further aggravate the inflammatory progression of psoriatic lesions through a crosstalk between keratinocytes and immune cells 21 . Besides IL-17 and cytokines such as IL-12 and IL-23 6 , IL-36 cytokines are important in psoriasis [24][25][26][27][28][29][30] . This is supported by our observations that IL-36 cytokines are induced in response to IL-17A in NHEKs, both in 3D models and in monolayer cultures, and that IL-36 inhibited keratinocyte differentiation in 3D models (Figs 1-3 and Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Members of the IL-36 family, which are IL-1 type cytokines, have also been implicated in psoriasis 22,23 . IL-36 cytokines are involved in the crosstalk between immune cells and keratinocytes and thus are potentially participating in controling the proinflammatory milieu in psoriatic skin [24][25][26][27][28][29][30] . Moreover, interaction of IL-17 and IL-36 has been postulated to promote inflammation 26,31 .…”

mentioning

confidence: 99%

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

Pfaff

Kluwig

Marquardt

et al. 2017

Journal of Investigative Dermatology

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Psoriasis is a T H 17-driven inflammatory disease affecting a significant proportion of the world population. The molecular consequences of IL-17 signaling in the skin are only partially understood. Therefore, we evaluated the IL-17A effects on organotypic 3-dimensional skin models and observed that IL-17A interfered with keratinocyte differentiation. In agreement with this phenotype, IL-17A repressed the expression of many genes encoding structural proteins. Moreover, genes encoding anti-microbial peptides were induced, resulting in a strengthening of the chemical barrier. Finally, we observed enhanced expression of the three IL-36 cytokines IL-36α, β and γ. We found that IL-36γ was secreted from keratinocytes in an inactive form and that neutrophilic proteases, including elastase, were capable of activating this cytokine. Functionally and similar to IL-17A, truncated IL-36 cytokines interfered with keratinocyte differentiation in 3D models. The molecular analysis revealed strong cooperative effects of IL-17A and IL-36 cytokines in regulating target genes, which was dependent on the proteolytic activation of the latter. Together these findings suggest an amplification cycle that can be initiated by IL-17A, involving IL-36 cytokines and immune cell derived proteases and resulting in active IL-36 cytokines which synergize with IL-17A. This amplification cycle might be relevant for a persistent psoriatic phenotype.Psoriasis, a chronic autoimmune disease of the skin, affects approximately 2% of the population. Psoriasis is associated with systemic inflammatory processes including inflammatory arthritis, inflammatory bowel disease, and metabolic syndrome 1,2 . A typical manifestation of the disease is the hyperproliferation of keratinocytes with premature differentiation. This results in incomplete cornification with retention of nuclei in the stratum corneum, referred to as parakeratosis. Functionally this correlates with increased infiltrations of immune cells due to dendritic cells, macrophages, neutrophils and different subpopulations of T cells. These cells modify the cytokine milieu and thus affect the behavior of keratinocytes resulting in altered differentiation [1][2][3]

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IL-36γ (IL-1F9) Is a Biomarker for Psoriasis Skin Lesions

Cited by 223 publications

References 37 publications

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

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

301 The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function

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