Journal Article

Impaired expression of metallothioneins contributes to allergen-induced inflammation in patients with atopic dermatitis

Horswill, Sarah, Corden, Emma, Clayton, Kalum, Roberts, Graham, Davies, James, Seaby, Eleanor G., Loxham, Matthew, Healy, Eugene, Singh, Harinder, Lai, Chester, Alyami, Rfeef, Polak, Marta E., Hall, Nigel J., Ennis, Sarah, Friedmann, Peter S., Sirvent, Sofia, Douilhet, Gemma, Vallejo, Andres F., Bennett, Clare L., Teo, Ying, Ardern-Jones, Michael R, Dean, Lareb S. N.

2023

Overview

Regulation of cutaneous immunity is severely compromised in inflammatory skin disease. To investigate the molecular crosstalk underpinning tolerance versus inflammation in atopic dermatitis, we utilise a human in vivo allergen challenge study, exposing atopic dermatitis patients to house dust mite. Here we analyse transcriptional programmes at the population and single cell levels in parallel with immunophenotyping of cutaneous immunocytes revealed a distinct dichotomy in atopic dermatitis patient responsiveness to house dust mite challenge. Our study shows that reactivity to house dust mite was associated with high basal levels of TNF-expressing cutaneous Th17 T cells, and documents the presence of hub structures where Langerhans cells and T cells co-localised. Mechanistically, we identify expression of metallothioneins and transcriptional programmes encoding antioxidant defences across all skin cell types, that appear to protect against allergen-induced inflammation. Furthermore, single nucleotide polymorphisms in the MTIX gene are associated with patients who did not react to house dust mite, opening up possibilities for therapeutic interventions modulating metallothionein expression in atopic dermatitis. Inflammatory skin diseases are frequently associated with dysregulation of cutaneous immunity. Here the authors perform human challenge with house dust mite allergen in patients with atopic dermatitis and explore the molecular network determining tolerance versus inflammation and identify a role for metallothioneins in the modulation of allergen induced inflammation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 13/51 / 13/62 / 13/89 / 38/39 / 38/77 / 38/88 / 38/91 / 45/43 / 631/250/24/2510 / 631/250/249/2510/1415 / 631/553 / 692/308/1426 / Allergens / Animals / Atopic dermatitis / Crosstalk / Dermatitis / Dermatitis, Atopic - genetics / Dust / Eczema / Helper cells / House dust / Human performance / Humanities and Social Sciences / Humans / Immunity / Immunological tolerance / In vivo methods and tests / Inflammation / Inflammation - genetics / Langerhans cells / Lymphocytes / Lymphocytes T / Metallothionein / Metallothioneins / Mites / multidisciplinary / Nucleotides / Pyroglyphidae / Science / Science (multidisciplinary) / Single-nucleotide polymorphism / Skin / Skin diseases / Therapeutic applications