期刊
JCI INSIGHT
卷 6, 期 21, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.149953
关键词
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资金
- NIH/National Institute of Allergy and Infectious Diseases (NIAID) Atopic Dermatitis Research Network grant [U19AI117673]
- NIH [AI113294-01A1]
- NIAID T32 training grant [5T32AI007512-32]
- CONACYT (Mexico)
- Boston Children's Hospital OFD/BTREC/CTREC Faculty Career Development Fellowship
- NIH/National Cancer Institute Cancer Center Support Grant [NIH 5 P30 CA06516]
Research has shown that mechanical injury to mouse skin through tape stripping predisposes the skin to superficial infection with S. aureus. This infection is promoted by basophil-derived IL-4, which inhibits the production of IL-17A and facilitates S. aureus infection. IL-4 acts on multiple checkpoints to suppress the cutaneous IL-17A response, but blocking the IL-4 receptor can enhance Il17a expression and bacterial clearance.
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 TCR gamma delta(+) 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 TCR gamma delta(+) 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 TCR gamma delta(+) 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.
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