Atopic dermatitis and inflammatory skin disease
Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses

https://doi.org/10.1016/j.jaci.2019.11.047Get rights and content

Background

Although multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity.

Objectives

We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD.

Methods

We analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings.

Results

Our data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, TH1, TH2, and TH17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of TH1, TH2, and TH17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator.

Conclusions

Our results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened TH2, TH1, TH17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting.

Section snippets

Skin biopsies and RNA-sequencing

Intrapersonal acute, chronic (>72-hour duration), and nonlesional (≥10 cm from active lesions) skin biopsies were collected from 11 consented white patients with moderate to severe AD, along with biopsies from 38 healthy volunteers included in a previous skin transcriptome study8 under an Institutional Review Board–approved protocol (A110/12) (see Table E1 in this article’s Online Repository at www.jacionline.org). In all patients, biopsies were taken from the upper arms (flexural side). No

Results

We performed RNA-sequencing on biopsies from nonlesional and paired acute and chronic lesions, enabling us to conduct robust analysis of differences and potential progression from nonlesional to acute to chronic stages of inflammation. We were able to profile 31,207 genes with an average of at least 1 read/sample. Notably, the top 3 principal components were not able to separate acute from chronic AD (Fig 1, A). A previous microarray-based study using less stringent criteria (ie, |log2 FC| ≥

Discussion

Clinically, AD presents with eczematous lesions in different acuity stages. Acute and chronic lesions are often found in the same individual, often overlap, and clinically are sometimes difficult to distinguish.24 Histologically, acute and chronic AD have fairly distinctive features. For instance, acute AD lesions exhibit spongiosis with mild to moderate acanthosis in addition to a superficial perivascular infiltrate of lymphocytes and macrophages. Mast cells show degranulation,25 and

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    This work was supported by BIOMAP (Biomarkers in Atopic Dermatitis and Psoriasis), a project funded by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 821511 and in-kind contributions of the participating pharma companies. The Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. It further received support from the Babcock Endowment Fund (L.C.T., M.K.S., J.E.G.), the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award numbers R01-AR060802 (J.E.G.), P30-AR075043 (J.E.G.), and K01-AR072129 (L.C.T.), and the National Institute of Allergy and Infectious Diseases under award number R01-AR069071 (J.E.G.), the A. Alfred Taubman Medical Research Institute (J.E.G. and J.M.K.), and the Kenneth and Frances Eisenberg Emerging Scholar Award (J.E.G.). L.C.T. is supported by the Dermatology Foundation, the Arthritis National Research Foundation, and the National Psoriasis Foundation. Infrastructure support was provided through the DFG Cluster of Excellence ‘‘Precision Medicine in Inflammation’’ (grant no. EXC2167).

    Disclosure of potential conflict of interest: J. M. Kahlenberg serves as advisory boards and received consulting fees from AstraZeneca, BMI, BMS, and Eli Lilly, and also received grant funding from Celgene/BMS. J. E. Gudjonsson received research grants from AbbVie, AnaptysBio, Pfizer, Novartis, Celgene, and Eli Lilly, and serves as advisory board member in Novartis, AbbVie, Eli Lilly, MiRagen, and Almirall. S. Weidinger has received institutional research grants from Novartis, Pfizer, and L’Oreal; has performed consultancies for Sanofi-Genzyme, Regeneron, LEO Pharma, Incyte, Lilly, AbbVie, and Novartis; has lectured at educational events sponsored by Sanofi-Genzyme, Regeneron, LEO Pharma, AbbVie, and Galderma; and is involved in performing clinical trials with pharmaceutical industries that manufacture drugs used for the treatment of atopic dermatitis. The rest of the authors declare that they have no relevant conflicts of interest.

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