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 White; Emanual Maverakis; Johann E. Gudjonsson; Stephan Weidinger

doi:10.1016/j.jaci.2019.11.047

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

^*Corresponding author for this work

Dermatology

Research output: Contribution to journal › Article › peer-review

126 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, T_H1, T_H2, and T_H17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of T_H1, T_H2, and T_H17 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 T_H2, T_H1, T_H17, 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 language	English (US)
Pages (from-to)	1406-1415
Number of pages	10
Journal	Journal of Allergy and Clinical Immunology
Volume	145
Issue number	5
DOIs	https://doi.org/10.1016/j.jaci.2019.11.047
State	Published - May 2020

Funding

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. 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).

Keywords

Atopic dermatitis
RNA-sequencing
acute AD
chronic AD
nonlesional

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. (2020). Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses. Journal of Allergy and Clinical Immunology, 145(5), 1406-1415. https://doi.org/10.1016/j.jaci.2019.11.047

@article{959a005799644750a9e7ad0adeec3a9a,

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

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.",

keywords = "Atopic dermatitis, RNA-sequencing, acute AD, chronic AD, nonlesional",

author = "Tsoi, {Lam C.} and Elke Rodriguez and Dora St{\"o}lzl and Ulrike Wehkamp and Jingru Sun and Sascha Gerdes and Sarkar, {Mrinal K.} and Matthias H{\"u}benthal and Chang Zeng and Ranjitha Uppala and Xianying Xing and Frederieke Thielking and Billi, {Allison C.} and Swindell, {William R.} and Alanna Shefler and Jiahan Chen and Patrick, {Matthew T.} and Harms, {Paul W.} and Kahlenberg, {J. Michelle} and {Perez White}, {Bethany E.} and Emanual Maverakis and Gudjonsson, {Johann E.} and Stephan Weidinger",

note = "Publisher Copyright: {\textcopyright} 2019 American Academy of Allergy, Asthma & Immunology",

year = "2020",

month = may,

doi = "10.1016/j.jaci.2019.11.047",

language = "English (US)",

volume = "145",

pages = "1406--1415",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby Inc.",

number = "5",

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Tsoi, LC, Rodriguez, E, Stölzl, D, Wehkamp, U, Sun, J, Gerdes, S, Sarkar, MK, Hübenthal, M, Zeng, C, Uppala, R, Xing, X, Thielking, F, Billi, AC, Swindell, WR, Shefler, A, Chen, J, Patrick, MT, Harms, PW, Kahlenberg, JM, Perez White, BE, Maverakis, E, Gudjonsson, JE & Weidinger, S 2020, 'Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses', Journal of Allergy and Clinical Immunology, vol. 145, no. 5, pp. 1406-1415. https://doi.org/10.1016/j.jaci.2019.11.047

TY - JOUR

T1 - Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses

AU - Tsoi, Lam C.

AU - Rodriguez, Elke

AU - Stölzl, Dora

AU - Wehkamp, Ulrike

AU - Sun, Jingru

AU - Gerdes, Sascha

AU - Sarkar, Mrinal K.

AU - Hübenthal, Matthias

AU - Zeng, Chang

AU - Uppala, Ranjitha

AU - Xing, Xianying

AU - Thielking, Frederieke

AU - Billi, Allison C.

AU - Swindell, William R.

AU - Shefler, Alanna

AU - Chen, Jiahan

AU - Patrick, Matthew T.

AU - Harms, Paul W.

AU - Kahlenberg, J. Michelle

AU - Perez White, Bethany E.

AU - Maverakis, Emanual

AU - Gudjonsson, Johann E.

AU - Weidinger, Stephan

PY - 2020/5

Y1 - 2020/5

N2 - 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.

AB - 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.

KW - Atopic dermatitis

KW - RNA-sequencing

KW - acute AD

KW - chronic AD

KW - nonlesional

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UR - http://www.scopus.com/inward/citedby.url?scp=85078828653&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2019.11.047

DO - 10.1016/j.jaci.2019.11.047

M3 - Article

C2 - 31891686

AN - SCOPUS:85078828653

SN - 0091-6749

VL - 145

SP - 1406

EP - 1415

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 5

ER -

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

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