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

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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.

Authors

Tomofumi Numata, Michael Shia, Yoshiyuki Nakamura, Fengwu Li, Hung Chan, Teruaki Nakatsuji, Kellen J. Cavagnero, Jared Simmons, Henry Li, Aaroh Anand Joshi, Marta Palomo-Irigoyen, Richard L. Gallo