The staphylococcal protease SspA perturbs the epidermal barrier and promotes IL-22-driven inflammation in allergen-exposed skin

Skin colonization by Staphylococcus aureus has emerged as a common feature of atopic dermatitis and other allergic diseases, yet it remains unclear how this bacterium contributes to inflammation and pathology. Our S. aureus secretome analysis and bioactivity-guided fractionation uncover that the serine protease SspA destroys keratinocyte junctions, increases epidermal permeability, and activates an epithelial inflammatory program linked to barrier dysfunction. SspA and house dust mite extract (HDM), when epicutaneously applied in combination, cause interleukin (IL)-22-dependent atopic dermatitis-like skin disease in mice. Spatial single-cell analysis and immunophenotyping of lesional skin of these mice reveal massive elongation and branching of epidermal nerve fibers and the formation of T cells simultaneously producing IL-13 and IL-22. Chemical denervation and the resultant dismantling of the neuroimmune signaling network reverse the pathology driven by SspA–HDM combination. These findings link S. aureus colonization to barrier perturbation, allergen sensitization, and neurogenic dermatitis.