Influence of FLG loss-of-function mutations in host–microbe interactions during atopic skin inflammation

Peter Oláh, Eszter Szlávicz, Marcus Kuchner, Jana Nemmer, Patrick Zeeuwen, Alain Lefèvre-Utile, Nanna Fyhrquist, Stefanie Prast-Nielsen, Tiina Skoog, Angela Serra, Elke Rodríguez, Ulrike Raap, Stephan Meller, Rolland Gyulai, Philippe Hupé, Juha Kere, Francesca Levi-Schaffer, Sophia Tsoka, Helen Alexander, Frank O. NestleJens M. Schröder, Stephan Weidinger, Ellen van den Bogaard, Vassili Soumelis, Dario Greco, Jonathan Barker, Antti Lauerma, Annamari Ranki, Björn Andersson, Harri Alenius, Bernhard Homey*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Background: Loss-of-function mutations in the filaggrin (FLG) gene directly alter skin barrier function and critically influence atopic inflammation. While skin barrier dysfunction, Th2-associated inflammation and bacterial dysbiosis are well-known characteristics of atopic dermatitis (AD), the mechanisms interconnecting genotype, transcriptome and microbiome remain largely elusive. Objective: In-depth analysis of FLG genotype-associated skin gene expression alterations and host-microbe interactions in AD. Methods: Multi-omics characterization of a cohort of AD patients carrying heterozygous loss-of-function mutations in the FLG gene (ADMut) (n = 15), along with matched wild-type (ADWt) patients and healthy controls. Detailed clinical characterization, microarray gene expression and 16 S rRNA-based microbial marker gene data were generated and analyzed. Results: In the context of filaggrin dysfunction, the transcriptome was characterized by dysregulation of barrier function and water homeostasis, while the lesional skin of ADWt demonstrated the specific upregulation of pro-inflammatory cytokines and T-cell proliferation. S. aureus dominated the microbiome in both patient groups, however, shifting microbial communities could be observed when comparing healthy with non-lesional ADWt or ADMut skin, offering the opportunity to identify microbe-associated transcriptomic signatures. Moreover, an AD core signature with 28 genes, including CCL13, CCL18, BTC, SCIN, RAB31 and PCLO was identified. Conclusions: Our integrative approach provides molecular insights for the concept that FLG loss-of-function mutations are a genetic shortcut to atopic inflammation and unravels the complex interplay between genotype, transcriptome and microbiome in the human holobiont.

Original languageEnglish
Pages (from-to)132-140
Number of pages9
JournalJournal of Dermatological Science
Volume106
Issue number3
DOIs
Publication statusPublished - Jun 2022

Keywords

  • Atopic dermatitis
  • Barrier function
  • Filaggrin
  • Microbiome
  • Multi-omics
  • Transcriptome

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