Environment impacts the phenotypic severity of flaky tail, MC903-induced inflammation, and dysbiosis in filaggrin-null mice

Document Type

Conference Proceeding

Publication Date

8-1-2024

Publication Title

J Invest Dermatol

Abstract

Atopic dermatitis (AD) is prevalent world-wide and is associated with population-specific FLG loss-of-function (LOF) variants. Filaggrin-null (Flg-/-) mice exhibit epicutaneous sensitization and increased permeability thus demonstrating a pathogenic role for filaggrin-deficient barrier impairment in AD. Yet we have a poor understanding of how FLG-deficient skin responds to differing environments. Here we examined the impact of housing Flg-/- adult mice in two geographically distinct animal facilities and compared their MC903-AD inducing skin inflammatory responses and scRNA-seq and flow cytometry analyses. Flg-/- mice originally housed in animal facility A exhibited no flaky tail or dry scaly skin yet with increased Streptococcus phyla dysbiosis. By contrast, Flg-/- mice housed in facility B exhibited flaky skin and tails as early as post-natal day (PND) 3 but resolved by PND16. Daily MC903 treatment resulted in significantly higher ear skin inflammation in both Flg-/- A and B mice each compared to wild-type (WT), house-matched controls (p<0.05). However, Flg-/- B-housed mice exhibited ear thickness and a rate of inflammation that was significantly higher (both 1.5 fold) compared to Flg-/- A mice (p<0.05). scRNA-seq identified 21 cell clusters (8 keratinocyte, 3 fibroblast, and 10 immune cell types; Seurat) in pooled MC903-treated ear skin of Flg-/-, Flg+/-, and WT B-housed mice. DEXseq confirmed significant decrease in Flg exon2-3 reads in Flg-/- MC903 ear skin scRNA-seq with notable increased IL7R+ Langerhans cells and CD74+ macrophages and CD3 Tregs that was confirmed by flow cytometry.Together, our findings reveal an environmental impact on flaky tail and increased MC903 inflammation severities in Flg-/- mice.

Volume

144

First Page

S67

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