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

Sofia Sirvent, Andres F. Vallejo, Emma Corden, Ying Teo, James Davies, Kalum Clayton, Eleanor G. Seaby, Chester Lai, Sarah Ennis, Rfeef Alyami, Gemma Douilhet, Lareb S. N. Dean, Matthew Loxham, Sarah Horswill, Eugene Healy, Graham Roberts, Nigel J. Hall, Peter S. Friedmann, Harinder Singh, Clare L. Bennett, Michael R Ardern-Jones and Marta E. Polak ()
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Sofia Sirvent: University of Southampton
Andres F. Vallejo: University of Southampton
Emma Corden: University Hospital Southampton NHS Foundation Trust
Ying Teo: University of Southampton
James Davies: University of Southampton
Kalum Clayton: University of Southampton
Eleanor G. Seaby: University of Southampton
Chester Lai: University of Southampton
Sarah Ennis: University of Southampton
Rfeef Alyami: University of Southampton
Gemma Douilhet: University of Southampton
Lareb S. N. Dean: University of Southampton
Matthew Loxham: University of Southampton
Sarah Horswill: University Hospital Southampton NHS Foundation Trust
Eugene Healy: University of Southampton
Graham Roberts: University Hospital Southampton NHS Foundation Trust
Nigel J. Hall: University Hospital Southampton NHS Foundation Trust
Peter S. Friedmann: University of Southampton
Harinder Singh: The University of Pittsburgh
Clare L. Bennett: University College London (UCL) Cancer Institute
Michael R Ardern-Jones: University of Southampton
Marta E. Polak: University of Southampton

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38588-1

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