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
γδ
+
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
γδ
+
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
γδ
+
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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