Atopic dermatitis and skin disease
Toll-like receptor 2 ligands promote chronic atopic dermatitis through IL-4–mediated suppression of IL-10

https://doi.org/10.1016/j.jaci.2014.02.017Get rights and content

Background

Atopic dermatitis (AD) is a T cell–mediated inflammatory skin disease, with TH2 cells initiating acute flares. This inflamed skin is immediately colonized with Staphylococcus aureus, which provides potent Toll-like receptor (TLR) 2 ligands. However, the effect of TLR2 ligands on the development of TH2-mediated AD inflammation remains unclear.

Objective

We investigated the progression of TH2 cell–mediated dermatitis after TLR2 activation.

Methods

Using models for acute AD with TH2 cells initiating cutaneous inflammation, we investigated the consequences of TLR2 activation. Dermatitis, as assessed by changes in ear skin thickness and histology, was analyzed in different BALB/c and C57BL/6 wild-type and knockout mouse strains, and immune profiling was carried out by using in vitro and ex vivo cytokine analyses.

Results

We show that TH2 cell–mediated dermatitis is self–limiting and depends on IL-4. Activation of TLR2 converted the limited TH2 dermatitis to chronic cutaneous inflammation. We demonstrate that the concerted activation of TLR2 and IL-4 receptor on dendritic cells is sufficient for this conversion. As an underlying mechanism, we found that the combinatorial sensing of the innate TLR2 ligands and the adaptive TH2 cytokine IL-4 suppressed anti-inflammatory IL-10 and consequently led to the exacerbation and persistence of dermatitis.

Conclusion

Our data demonstrate that innate TLR2 signals convert transient TH2 cell–mediated dermatitis into persistent inflammation, as seen in chronic human AD, through IL-4–mediated suppression of IL-10. For the first time, these data show how initial AD lesions convert to chronic inflammation and provide another rationale for targeting IL-4 in patients with AD, a therapeutic approach that is currently under development.

Section snippets

Mice

BALB/c, C57BL/6, DO11.10, OT-II, and signal transducer and activator of transcription 6 (Stat6)–deficient mice were purchased from Charles River (Sulzfeld, Germany) or the Jackson Laboratory (Bar Harbor, Me). Tlr2−/− BL/6 mice were provided by C. Kirschning (Duisburg, Germany) and backcrossed to the BALB/c background, MHCII−/− mice were provided by L. Klein (Munich, Germany), and Il4ra−/− mice were provided by A. Gessner (Erlangen, Germany). All mice were kept and bred under specific

Self-limited allergen-induced dermatitis is mediated by IL-4

Early immune reactions in AD skin are dominated by TH2 cells and cytokines and are believed to predispose the AD skin for colonization by bacteria, such as S aureus. As a model for the early phase of AD inflammation, OVA-specific IL-4–producing TH2 cells were intracutaneously transferred with or without OVA into the ears of naive mice. Ear swelling was determined as the change in skin thickness to quantify dermatitis. Transfer of TH2 cells with OVA provoked strong but self-limiting cutaneous

Discussion

AD is based on a complex genetic trait, with skin barrier defects being among the most frequent functional abnormalities.3, 28 The majority of patients with AD have increased IgE levels toward environmental antigens and TH2-biased T-cell immunity, which is based on both cutaneous barrier defects and an inherent immune bias toward TH2 immunity.2 A prerequisite for the development of AD inflammation is the initial recruitment of IL-4–producing TH2 cells to the skin on acute triggering factors,

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    Supported by contract research “Allergologie 2” of the Baden-Württemberg Stiftung (P-LS-AL2/4) and by grants of the Deutsche Forschungsgemeinschaft (DFG; BI696/10-1, B1696/5-1, BI696/5-2, SFB 685 A06, C01) and the Wilhelm Sander-Stiftung (2012.056.1).

    Disclosure of potential conflict of interest: S. Kaesler has received research support from Deutsche Forschungsgemeinschaft and Landesstiftung Baden-Württemberg. Y. Skabytska has received research support from Deutsche Forschungsgemeinschaft (DFG; BI 696/10-1). M. Köberle has received research support from Deutsche Forschungsgemeinschaft (DFG BI 696/5-1 and DFG BI 696/5-2). K.-M. Chen has received research support from Baden-Württemberg Stiftung. E. Guenova is employed by Harvard Medical School/Brigham and Women's Hospital and has received research support from the German Research Foundation (GU1271/2-1). M. Röcken has received research support from Abbott Laboratories, Abbott Pharmaceuticals, Almirall Hermal, Bayer, Biogen, Bundesministerium für Bildung und Forschung, Celgene, Deutsche Dermatologische Gesellschaft, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, the European Union, Galderma, GlaxoSmithKline, Hokusai, Janssen Cilag, Johnson & Johnson, Lilly, MSD Sharp & Dohme, Novartis, Pfizer, Roche, Wilhelm Sander-Stiftung, AstraZeneca, Bristol-Myers Squibb, Philogen, and AB Science and has received personal fees from Almirall Hermal, Bayer Healthcare, Biogen Idec, MSD Sharp & Dohme, Regeneron, and Roche. T. Biedermann has received research support from Baden-Württemberg Stiftung and Deutsche Forschungsgemeinschaft; has received consultancy fees from Meda and Novartis; and has received personal fees from Janssen Cilag, ALK-Abelló, Biogen, Meda, Novartis, and Phadia/Thermo Fisher. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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