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

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.

• Authors: 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 Nestle, Jens M Schröder, Stephan Weidinger, Ellen van den Bogaard, Vassili Soumelis, Dario Greco, Jonathan Barker, Antti Lauerma, Annamari Ranki, Björn Andersson, Harri Alenius, Bernhard Homey
• Journal: Journal of dermatological science (J Dermatol Sci) Vol. 106 Issue 3 Pg. 132-140 (Jun 2022) ISSN: 1873-569X [Electronic] Netherlands
• PMID: 35537882 (Publication Type: Journal Article)
• Copyright: Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.

Chemical References

• FLG protein, human
• Filaggrin Proteins
• Intermediate Filament Proteins

Topics

• Dermatitis, Atopic (metabolism)
• Filaggrin Proteins (metabolism)
• Host Microbial Interactions (genetics)
• Humans
• Inflammation (genetics, metabolism)
• Intermediate Filament Proteins (genetics, metabolism)
• Mutation
• Skin (metabolism)
• Staphylococcus aureus