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 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 2022;106(3):132-140

PMID: 35537882

Full Text on Elsevier Science View on PubMed

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 (AD) (n = 15), along with matched wild-type (AD) 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 AD 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 AD or AD 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.

Address: Department of Dermatology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany; Department of Dermatology, Venereology and Oncodermatology, Medical Faculty, University of Pécs, Hungary.; Department of Dermatology, Venereology and Oncodermatology, Medical Faculty, University of Pécs, Hungary.; Department of Dermatology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany.; Department of Dermatology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.; Université de Paris, Inserm, U976 HIPI Unit, Institut de Recherche Saint-Louis, Paris, France; Assistance Publique-Hôpitaux de Paris (APHP), General Pediatric and Pediatric Emergency Department, Jean Verdier Hospital, Bondy, France.; Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; Centre for Translational Microbiome Research (CTMR), Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.; Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Institute of Biosciences and Medical Technologies (BioMediTech), Tampere, University, Finland.; Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany.; Department of Dermatology, University Hospital Oldenburg, Germany.; INSERM U900, CNRS UMR144, Institut Curie, Mine Paris Tech, Paris, France.; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Stem Cells and Metabolism Research Program, Folkhälsan Research Institute, University of Helsinki, Helsinki, Finland.; Pharmacology and Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.; Department of Informatics, Faculty of Natural and Mathematical Sciences, Kings College London, London, United Kingdom.; St John's Institute of Dermatology, Faculty of Medicine and Life Sciences, Kings College London, London, United Kingdom.; Université de Paris, Inserm, U976 HIPI Unit, Institut de Recherche Saint-Louis, Paris, France; Laboratoire d'Immunologie et Histocompatibilité, AP-HP, Hôpital St Louis, Paris, France.; Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Institute of Biosciences and Medical Technologies (BioMediTech), Tampere, University, Finland; Institute of Biotechnology, University of Helsinki, Helsinki, Finland.; Department of Dermatology, Allergology and Venereology, Inflammation Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.; Department of Dermatology, University Hospital Duesseldorf, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany. Electronic address: [email protected].

DOI: 10.1016/j.jdermsci.2022.04.007

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MeSH Terms: Dermatitis, Atopic, Filaggrin Proteins, Host Microbial Interactions, Humans, Inflammation, Intermediate Filament Proteins, Mutation, Skin, Staphylococcus aureus