Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses

Lam C. Tsoi, Elke Rodriguez, Dora Stölzl, Ulrike Wehkamp, Jingru Sun, Sascha Gerdes, Mrinal K. Sarkar, Matthias Hübenthal, Chang Zeng, Ranjitha Uppala, Xianying Xing, Frederieke Thielking, Allison C. Billi, William R. Swindell, Alanna Shefler, Jiahan Chen, Matthew T. Patrick, Paul W. Harms, J. Michelle Kahlenberg, Bethany E. Perez WhiteEmanual Maverakis, Johann E. Gudjonsson, Stephan Weidinger

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
DOIs
StateAccepted/In press - Jan 1 2020

Keywords

  • acute AD
  • Atopic dermatitis
  • chronic AD
  • nonlesional
  • RNA-sequencing

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Tsoi, L. C., Rodriguez, E., Stölzl, D., Wehkamp, U., Sun, J., Gerdes, S., Sarkar, M. K., Hübenthal, M., Zeng, C., Uppala, R., Xing, X., Thielking, F., Billi, A. C., Swindell, W. R., Shefler, A., Chen, J., Patrick, M. T., Harms, P. W., Kahlenberg, J. M., ... Weidinger, S. (Accepted/In press). Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2019.11.047