Detection of IL-36γ through noninvasive tape stripping reliably discriminates psoriasis from atopic eczema

Berekméri, Anna; Latzko, Anne; Alase, Adewonuola; Macleod, Tom; Ainscough, Joseph S.; Laws, Philip; Goodfield, Mark; Wright, Andrew; Helliwell, Philip; Edward, Sara; Brown, Gordon D.; Reid, Delyth M.; Wenzel, Joerg; Stacey, Martin; Wittmann, Miriam

doi:10.1016/j.jaci.2018.04.031

Cited by 26 publications

(27 citation statements)

References 12 publications

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“…IL-36γ signals through IL-36R and IL-1RAcP to activate the pathway leading to NF-κB and MAPKs 18. IL-36γ immunohistochemistry was found to be a useful marker in the histological differential diagnosis between psoriasis and eczema,8 and detection of IL-36γ protein through noninvasive tape stripping of lesion credibly differentiates psoriasis from atopic eczema 19…”

Section: Discussionmentioning

confidence: 98%

<p>Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis</p>

Guo¹,

Tu²,

Hu³

et al. 2019

DDDT

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BackgroundIL-36γ is considered to be a valuable biomarker in psoriatic patients, which is expressed as an inactive precursor that needs to be proteolytically processed and activated, and neutrophil-derived proteases seemed to be potent activating enzymes of IL-36γ.ObjectivesThis study aims to investigate the activation of IL-36γ by cathepsin G (CG) and neutrophil elastase (NE).Materials and methodsWe used inactive recombinant full-length (FL)-IL-36γ with different doses of NE or CG to stimulate HaCaT cells; neutrophil extracellular traps (NETs) were prepared to act on FL-IL-36γ and then stimulate HaCaT cells. Real-time quantitative PCR and ELISA were performed to detect CXCL-1 and CXCL-8 expression. We developed imiquimod-induced psoriasis-like mouse model to evaluate the effect of hypodermic injection of neutrophil-derived protease or its inhibitor. Histopathology and Western blotting were conducted for effect assessment.ResultsPurified CG cleaved and activated recombinant human FL-IL-36γ to promote CXCL-1 and CXCL-8 expression by human keratinocytes, and NETs activated FL-IL-36γ and the activation was inhibited by serpin A3. CG induced expression of a more truncated IL-36γ in psoriasiform lesion of mice and aggravated the psoriasis-like lesion induced by imiquimod, whereas recombinant serpin A3 alleviated the severity of the psoriasis-like mouse mode.ConclusionCG has the ability to cleave and activate IL-36γ and aggravate imiquimod-induced mouse psoriasiform lesion. Thus, CG-specific inhibitors might be promising therapeutic drugs for psoriasis.

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Section: Discussionmentioning

confidence: 98%

<p>Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis</p>

Guo¹,

Tu²,

Hu³

et al. 2019

DDDT

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“…Robust suppression of hallmark T H 17 genes (LCN, PI3/elafin, CCL20, S100As, IL36G, IL36RN, and IL19) might have implications for possible treatment of psoriasis, 97 acne vulgaris, [98][99][100] hidradenitis suppurativa, 101 ichthyoses, 102 and other T H 17-driven diseases. [10][11][12]103,104 Robust modulation of T H 17 is also emphasized by the greater inhibition of IL-17-induced release of CCL20 in keratinocytes by ASN002 compared with tofacitinib, a pan-JAK inhibitor, which indeed did not show robust T H 17/T H 22 modulation at week 2 in patients with psoriasis. 90 Our study had several limitations, including a small sample size, short study duration of only 4 weeks, and nonsignificant differences in baseline EASI scores between the groups (the 20and 80-mg groups were more severe with an EASI score of approximately 29, whereas the 40-mg and placebo groups had EASI scores of approximately 21), perhaps accounting for the greater clinical and biomarker effects seen in the 40-mg group versus the 80-mg group and the lack of efficacy in the 20-mg group.…”

Section: Discussionmentioning

confidence: 99%

Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis

Pavel

Song

Kim

et al. 2019

Journal of Allergy and Clinical Immunology

101

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Background: Moderate-to-severe atopic dermatitis (AD) has been associated with significant disease burden and systemic abnormalities and often requires systemic treatments. Currently, safe and effective oral systemic treatments for moderate-to-severe AD are not yet available. ASN002 is an oral inhibitor of the Janus kinase/spleen tyrosine kinase signaling pathways, targeting several cytokine axes (T H 2/T H 22/T H 17/T H 1) and epidermal differentiation. Objective: We sought to evaluate the effect of ASN002 on the cellular and molecular biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clinical severity measures and pruritus. Methods: Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. Gene expression studies were conducted by using microarray and quantitative RT-PCR, and cellular infiltrates and protein expression were studied by using immunohistochemistry. Results: ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including T H 2 (IL4 receptor [IL4R], IL13, CCL13/ monocyte chemoattractant protein 4, CCL17/thymus and activation-regulated chemokine, CCL18/pulmonary and activation-regulated chemokine, CCL22/macrophage-derived chemokine, and CCL26/eotaxin-3), T H 17/T H 22 (lipocalins, PI3/ elafin, CCL20, S100A7/S100A8/S100A9, and IL36G/IL36RN), and T H 1 (IFNG, CXCL9/CXCL11, and MX1) axes and barrierrelated measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were observed predominantly in the 40-and 80-mg groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups. Conclusion: The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD.

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“…Supernatants were analyzed for IL-8 protein using a specific ELISA kit from Biolegend (San Diego, CA). Supernatants and lysates were analyzed for IL-36γ protein using an in-house monoclonal based ELISA previously described ( Berekmeri et al., 2018 ). IL-8 ELISA was performed following the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…While many IL-1 cytokines can be found expressed throughout the body, the IL-36 cytokines are predominately expressed in epithelial tissue such as the skin, lungs, gut, and mucosa, particularly at apical locations, suggesting an important role in barrier immune function ( Dunn et al., 2001 ; Gabay and Towne, 2015 ; Boutet et al., 2016 ). Indeed, it is now well established that IL-36γ is a proinflammatory mediator highly expressed in psoriasis and is involved in the initiation and maintenance of pathological inflammation ( Johnston et al., 2011 ; He et al., 2013 ; Berekmeri et al., 2018 ; Bridgewood et al., 2018 ). However, this cytokine is also a critical mediator of immune responses to several classes of invading pathogens at epithelial barriers ( Kovach et al., 2017 ; Gao et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

The Proinflammatory Cytokine IL-36γ Is a Global Discriminator of Harmless Microbes and Invasive Pathogens within Epithelial Tissues

et al. 2020

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Summary Epithelial tissues represent vital interfaces between organisms and their environment. As they are constantly exposed to harmful pathogens, innocuous commensals, and environmental microbes, it is essential they sense and elicit appropriate responses toward these different types of microbes. Here, we demonstrate that the epithelial cytokine interleukin-36γ (IL-36γ) acts as a global discriminator of pathogenic and harmless microbes via cell damage and proteolytic activation. We show that intracellular pro-IL-36γ is upregulated by both fungal and bacterial epithelial microbes; yet, it is only liberated from cells, and subsequently processed to its mature, potent, proinflammatory form, by pathogen-mediated cell damage and pathogen-derived proteases. This work demonstrates that IL-36γ senses pathogen-induced cell damage and proteolytic activity and is a key initiator of immune responses and pathological inflammation within epithelial tissues. As an apically located epithelial proinflammatory cytokine, we therefore propose that IL-36γ is critical as the initial discriminator of harmless microbes and invasive pathogens within epithelial tissues.

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Detection of IL-36γ through noninvasive tape stripping reliably discriminates psoriasis from atopic eczema

Cited by 26 publications

References 12 publications

<p>Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis</p>

<p>Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis</p>

Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis

The Proinflammatory Cytokine IL-36γ Is a Global Discriminator of Harmless Microbes and Invasive Pathogens within Epithelial Tissues

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Detection of IL-36γ through noninvasive tape stripping reliably discriminates psoriasis from atopic eczema

Cited by 26 publications

References 12 publications

<p>Cathepsin G cleaves and activates IL-36&gamma; and promotes the inflammation of psoriasis</p>

<p>Cathepsin G cleaves and activates IL-36&gamma; and promotes the inflammation of psoriasis</p>

Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis

The Proinflammatory Cytokine IL-36γ Is a Global Discriminator of Harmless Microbes and Invasive Pathogens within Epithelial Tissues

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<p>Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis</p>

<p>Cathepsin G cleaves and activates IL-36γ and promotes the inflammation of psoriasis</p>