Dermal fibroblasts respond to IL-4 and IL-13 and promote T cell recruitment in atopic dermatitis.

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by a type 2 immune response that is not fully understood. Single-cell RNA-seq of human AD skin and murine models of type 2 inflammation identified transcriptionally distinct fibroblast clusters, revealing IL-4Rα-dependent populations of immune-acting fibroblasts (IAFs). These unbiased findings prompted further investigation into the role of dermal fibroblasts during allergic inflammation. These studies demonstrated that, in an inflammatory environment including TNF-α, IL-1β, and IL-17A, the cytokines IL-4 and IL-13 stimulated both mouse and human fibroblasts to produce multiple chemokines, including CCL8, which activated CCR3 to attract T cells. In the skin, fibroblasts were the primary source of many of these chemokines, and targeted deletion of IL-4Rα in mouse fibroblasts reduced T cell infiltration in a mouse model of AD. Additionally, pharmacologic inhibition of CCR3, the receptor shared by many chemokines produced by fibroblasts, decreased T cell infiltration and skin inflammation in mouse models of AD. These findings demonstrate that dermal fibroblasts are more than passive structural cells; they actively participate in the type 2 immune response and contribute to AD by producing chemokines that increase inflammation. Targeting the functions of IAFs could offer an alternative therapeutic approach for AD.