Cutaneous Immune Cell-Microbiota Interactions Are Controlled by Epidermal JunB/AP-1

Özge Uluçkan,Maria Jiménez,Ben Roediger,Jakob Schnabl,Lucía T Díez-Córdova,Kevin Troulé,Wolfgang Weninger,Erwin F Wagner

doi:10.1016/j.celrep.2019.09.042

Özge Uluçkan, Maria Jiménez + Show 6 more

Open Access

https://doi.org/10.1016/j.celrep.2019.09.042

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Abstract

SummaryAtopic dermatitis (AD) is a multi-factorial skin disease with a complex inflammatory signature including type 2 and type 17 activation. Although colonization by S. aureus is common in AD, the mechanisms rendering an organism prone to dysbiosis, and the role of IL-17A in the control of S. aureus-induced skin inflammation, are not well understood. Here, we show several pathological aspects of AD, including type 2/type 17 immune responses, elevated IgE, barrier dysfunction, pruritus, and importantly, spontaneous S. aureus colonization in JunBΔep mice, with a large transcriptomic overlap with AD. Additionally, using Rag1−/− mice, we demonstrate that adaptive immune cells are necessary for protection against S. aureus colonization. Prophylactic antibiotics, but not antibiotics after established dysbiosis, reduce IL-17A expression and skin inflammation, examined using Il17a-eGFP reporter mice. Mechanistically, keratinocytes lacking JunB exhibit higher MyD88 levels in vitro and in vivo, previously shown to regulate S. aureus colonization. In conclusion, our data identify JunB as an upstream regulator of microbiota-immune cell interactions and characterize the IL-17A response upon spontaneous dysbiosis.

Highlights

Atopic dermatitis (AD) is a debilitating, chronic inflammatory skin disease affecting 15%–20% of children and up to 10% of adults (Weidinger et al, 2018)
Colonization by S. aureus is common in AD, the mechanisms rendering an organism prone to dysbiosis, and the role of IL-17A in the control of S. aureus-induced skin inflammation, are not well understood
Using Rag1À/À mice, we demonstrate that adaptive immune cells are necessary for protection against S. aureus colonization

Summary

Introduction

Atopic dermatitis (AD) is a debilitating, chronic inflammatory skin disease affecting 15%–20% of children and up to 10% of adults (Weidinger et al, 2018). Consistent with this, recombinant IL-17A given at the time of S. aureus challenge rescues the increased inflammation observed in TCRgd T cell-deficient mice, suggesting a protective role of IL-17A in S. aureus-induced skin inflammation (Cho et al, 2010). IL-17A-secreting dendritic cells interacting with the skin microbiota have been shown to be essential to protect the skin from S. aureus infections (Naik et al, 2015). These studies suggest a protective role of IL-17A signaling in S. aureus colonization, through effects of the commensal bacteria. The role of IL-17 remains unclear in cutaneous dysbiosis and AD, and further studies are needed to better

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