IL-31 regulates differentiation and filaggrin expression in human organotypic skin models

Cornélissen, Christian; Marquardt, Yvonne; Czaja, Katharina; Wenzel, Joerg; Frank, Jorge; Lüscher-Firzlaff, Juliane; Lüscher, Bernhard; Baron, Jens Malte

doi:10.1016/j.jaci.2011.10.042

Cited by 253 publications

(239 citation statements)

References 48 publications

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“…To study IL-17A signaling in more detail, we measured its effects in NHEK monolayer cultures. Our previous studies with IL-31 had shown substantial differences in gene expression when 3D models and monolayer were compared 39,40 . In contrast to these findings, all genes tested could be verified in NHEK monolayers, including the AMP encoding genes S100A7, S100A7A, S100A8, S100A12, DEFB103A and DEFB4A, and the cytokine/chemokine genes IL36A, IL36B, IL36G, CXCL17, and IL24 (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…The cells were cultivated under standard cell culture conditions as described previously 54 . Organotypic 3 dimensional skin equivalents were constructed as described previously 39,54 , cultured at the air-liquid interphase, and treated with recombinant human (rh) IL-17A (Peprotech, Hamburg, Germany), truncated (t-)IL-36α/IL-1F6 (aa 6-158), t-IL-36β/IL-1F8 (aa 5-157) and t-IL-36γ/IL-1F9 (aa 18-169) (R&D, Minneapolis, USA). Secukinumab (aka Cosentyx ® , Novartis) was used as indicated in the figure legends, but typically at a concentration of 4.3 μg/ml, which correlates with the concentration used for clinical treatment (300 mg per day per patient (70 kg)).…”

Section: Methodsmentioning

confidence: 99%

“…For gene expression analysis, NHEK organotypic 3D skin equivalents were stimulated with IL-17A (50 ng/ml, PeproTech) for 24 h or 48 h. Then mRNA was isolated, purified and analyzed on GeneChip Human Exon 2.0 ST arrays as reported previously 39,40 . Data analysis was performed with GeneSpring GX 11 software (Agilent, Böblingen, Germany).…”

Section: Exon Expression Arraysmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Exon Expression Arraysmentioning

confidence: 99%

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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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“…The skin-infiltrating T lymphocytes are not only a source of Th2 cytokines, but also of other cytokines such as IFN-γ, IL-22, and IL-17 [18]. Expression of FLG by keratinocytes is diminished by Th2 and itch-related cytokines IL-4, IL-13, IL-31, and IL-33 [19][20][21] (Fig. 1).…”

Section: Interplay Between Systemic and Local Immune Responses In Admentioning

confidence: 99%

Atopic dermatitis: A tale of two distinct pathomechanisms that make you itch

Knol

Hijnen

2016

Eur J Immunol

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Atopic dermatitis (AD) or eczema is the most common chronic inflammatory skin disease, with an incidence of more than 10% in children [1], decreasing to about 3% in the adult population [2]. AD is a chronic disease that can be difficult to control, both due to patient treatment compliance, as well as the unremitting underlying inflammatory process. Moisturizing ointments and topical corticosteroids are the main treatments to minimize dryness and limit inflammation and itchiness in these patients. Recently, the biological dupilumab, an antibody which blocks the receptor for IL-4 and IL-13, has been demonstrated to be a very potent treatment modality in AD. The use of dupilumab has been a breakthrough in the implementation of more targeted treatment of AD [3].Correspondence: Dr. Edward F. Knol e-mail: e.f.knol@umcutrecht.nl It is clear that AD is the result of local, as well as systemic, pathomechanisms. However, AD is considered mainly a Th2-driven systemic disease due to the fact that it is strongly associated with other atopic diseases, i.e. allergic rhinoconjunctivitis, allergic asthma, and food allergy [4].The local skin response in AD Filaggrin (FLG) is an important structural protein required for epidermal barrier function through its role in the form and function of the stratum corneum [5]. Reduced FLG favors transepidermal water loss, allergen penetration and skin bacterial colonization [6]. Recently, it was demonstrated that FLG inhibits neo-antigen formation by the house-dust mite enzyme phospholipase [7]. It has been already known for some years that functional effects of profilaggrin and FLG loss in flaky tail mice results in a dry and flaky skin, resembling the skin of patients with ichthyosis vulgaris [8]. FLG-deficient mice displayed an increased permissiveness to epicutaneous sensitization with protein antigens such as ovalbumin [9]. FLG loss-of-function mutations are the strongest genetic risk factor in AD. It is estimated that up to 50% of patients with AD in diverse populations carry one or more FLG loss-of-function mutations [6]. It is also important to realize that, although null mutations in the FLG gene are the strongest and most reproducible genetic risk factors in AD in human, 60% of the carriers do not develop AD. In addition, more than half of the AD patients do not carry FLG mutations [6]. Therefore, other factors must also be involved in the pathogenesis of AD.The reduction in the integrity of the skin barrier results in increased penetration of allergens in the upper layers of the epidermis [9]. Subsequently, allergens are taken up by Langerhans cells, especially those that carry allergen-specific IgE on the high affinity Fc receptor for IgE (FcεRI), and then presented to T cells [10,11] (Fig. 1). The latter finding has frustrated the implication of rodent models for AD, because the FcεRI expression on antigen-presenting cells is much more difficult to establish in rodents [12]. Systemic immune responses in ADThere are marked immune responses in AD both within the innate and adaptiv...

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“…(14)(15)(16) (B) Expression of epidermal FLG is down regulated by cytokines IL-4, IL-13, IL-17A, IL-22, IL-25, IL-31, TNF-α in AD patients. (17)(18)(19)(20)(21)(22)(23) (C) Effect of environmental factors which lead to FLG proteolysis such as low ambient humidity, skin irritants, pruritus / excoriations / mechanical damage, age and water. (24,25) Later will be reviewed the genetic variation of FLG.…”

Section: Factors Influence On Skin Barrier Dysfunctionsmentioning

confidence: 99%

Molecular Genetic of Atopic Dermatitis : An Update

Al‐Shobaili

Ahmed

Alnomair

et al. 2016

IJHS

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Atopic dermatitis (AD) is a chronic multifactorial inflammatory skin disease. The pathogenesis of AD remains unclear, but the disease results from dysfunctions of skin barrier and immune response, where both genetic and environmental factors play a key role. Recent studies demonstrate the substantial evidences that show a strong genetic association with AD. As for example, AD patients have a positive family history and have a concordance rate in twins. Moreover, several candidate genes have now been suspected that play a central role in the genetic background of AD. In last decade advanced procedures similar to genome-wide association (GWA) and single nucleotide polymorphism (SNP) have been applied on different population and now it has been clarified that AD is significantly associated with genes of innate/adaptive immune systems, human leukocyte antigens (HLA), cytokines, chemokines, drug-metabolizing genes or various other genes. In this review, we will highlight the recent advancements in the molecular genetics of AD, especially on possible functional relevance of genetic variants discovered to date.

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IL-31 regulates differentiation and filaggrin expression in human organotypic skin models

Cited by 253 publications

References 48 publications

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

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

Atopic dermatitis: A tale of two distinct pathomechanisms that make you itch

Molecular Genetic of Atopic Dermatitis : An Update

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