Basophil-derived IL-4 promotes cutaneous Staphylococcus aureus infection.

Juan-Manuel Leyva-Castillo,Maria Strakosha,Lloyd S Miller,Sonal Singh,Jennifer Kane,Raif S Geha,Frank Brombacher,Alexander R Horswill,Hajime Karasuyama,Daniel Sen Hoi Wong,Mrinmoy Das

doi:10.1172/jci.insight.149953

Abstract

Superficial cutaneous Staphylococcus aureus (S. aureus) infection in humans can lead to soft tissue infection, an important cause of morbidity and mortality. IL-17A production by skin TCRγδ+ cells in response to IL-1 and IL-23 produced by epithelial and immune cells is important for restraining S. aureus skin infection. How S. aureus evades this cutaneous innate immune response to establish infection is not clear. Here we show that mechanical injury of mouse skin by tape stripping predisposed mice to superficial skin infection with S. aureus. Topical application of S. aureus to tape-stripped skin caused cutaneous influx of basophils and increased Il4 expression. This basophil-derived IL-4 inhibited cutaneous IL-17A production by TCRγδ+ cells and promoted S. aureus infection of tape-stripped skin. We demonstrate that IL-4 acted on multiple checkpoints that suppress the cutaneous IL-17A response. It reduced Il1 and Il23 expression by keratinocytes, inhibited IL-1+IL-23–driven IL-17A production by TCRγδ+ cells, and impaired IL-17A–driven induction of neutrophil-attracting chemokines by keratinocytes. IL-4 receptor blockade is shown to promote Il17a expression and enhance bacterial clearance in tape-stripped mouse skin exposed to S. aureus, suggesting that it could serve as a therapeutic approach to prevent skin and soft tissue infection.

Highlights

Staphylococcus aureus (S. aureus) is the most common causative agent of bacterial skin and soft tissue infections (SSTIs) [1,2,3]
Our results demonstrate that basophils are recruited following exposure of S. aureus on tapestripped skin and that basophil-derived IL-4 acts at multiple checkpoints to inhibit the IL-17A response of TCRγδ+ T cells that protects against infection
Like intradermal and subcutaneous infection with S. aureus, superficial S. aureus skin infection elicited a TCRγδ+ cell–dependent protective local IL-17A response that promoted neutrophil recruitment and antimicrobial peptides (AMPs) production, both of which are important for the clearance of S. aureus [7, 8, 14, 43]

Summary

Introduction

Staphylococcus aureus (S. aureus) is the most common causative agent of bacterial skin and soft tissue infections (SSTIs) [1,2,3]. IL-17A plays an important role in protection against mucosal infections, by recruiting neutrophils and promoting the production of antimicrobial peptides (AMPs) by epithelial cells [7, 8]. Patients and mice with defects in IL-17A, IL-17A receptor chains, or IL-17A signaling, or defects in neutrophil number or function, are susceptible to mucosal and skin infections caused by S. aureus [9,10,11]. IL-17A production by TCRγδ+ T cells and subsequent neutrophil recruitment to the skin play a critical role in controlling cutaneous S. aureus infection [7, 8, 11,12,13,14]. Patients and mice with defects in IL-1 and IL-23 production or signaling have defective IL-17A production and are susceptible to S. aureus infections [16,17,18,19,20,21,22]

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Results

Conclusion