Influence of FLG loss-of-function mutations in host–microbe interactions during atopic skin inflammation. Issue 3 (June 2022)

• Record Type: Journal Article
• Authors: Oláh, Peter; Szlávicz, Eszter; Kuchner, Marcus; Nemmer, Jana; Zeeuwen, Patrick; Lefèvre-Utile, Alain; Fyhrquist, Nanna; Prast-Nielsen, Stefanie; Skoog, Tiina; Serra, Angela; Rodríguez, Elke; Raap, Ulrike; Meller, Stephan; Gyulai, Rolland; Hupé, Philippe; Kere, Juha; Levi-Schaffer, Francesca; Tsoka, Sophia; Alexander, Helen; Nestle, Frank O.; Schröder, Jens M.; Weidinger, Stephan; van den Bogaard, Ellen; Soumelis, Vassili; Greco, Dario; Barker, Jonathan; Lauerma, Antti; Ranki, Annamari; Andersson, Björn; Alenius, Harri; Homey, Bernhard;
• Is Part Of: Journal of dermatological science. Volume 106:Issue 3(2022)
• Page Start: 132
• Page End: 140
• Publication Date: 2022-06
• Subjects: AD atopic dermatitis -- ADWt atopic dermatitis patients with wild-type FLG -- ADMut atopic dermatitis patients carrying loss-of-function FLG polymorphisms -- HV healthy volunteer -- FLG filaggrin -- 16 S rRNA 16 S ribosomal RNA subunit; Atopic dermatitis -- Barrier function -- Filaggrin -- Microbiome -- Multi-omics -- Transcriptome; Dermatology -- Periodicals; Skin Diseases -- Periodicals; Dermatologie -- Périodiques; 616.5005
• DOI: 10.1016/j.jdermsci.2022.04.007
• Languages: English
• ISSNs: 0923-1811

Abstract

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 Mut ) (n = 15), along with matched wild-type (AD Wt ) 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 Wt 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 Wt or AD Mut 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. Highlights: Eczema patients carrying filaggrin mutations present equal or moderately higher severity than matched wild-type patients. More extensive dysregulation of gene expression is present in filaggrin Wt lesions than in filaggrin Mut A lower threshold of onset in filaggrin Mut and a „longer route" required for the same manifestation in filaggrin Wt .