Microbial dysbiosis in the skin has been implicated in the pathogenesis of atopic dermatitis (AD); however, whether and how changes in the skin microbiome initiate skin inflammation, or vice versa, remains poorly understood. Here, we report that the levels of sebum and its microbial metabolite, propionate, were lower on the skin surface of AD patients compared with those of healthy individuals. Topical propionate application attenuated skin inflammation in mice with MC903-induced AD-like dermatitis by inhibiting IL-33 production in keratinocytes, an effect that was mediated through inhibition of HDAC and regulation of the AhR signaling pathway. Mice lacking sebum spontaneously developed AD-like dermatitis, which was improved by topical propionate application. A proof-of-concept clinical study further demonstrated the beneficial therapeutic effects of topical propionate application in AD patients. In summary, we have uncovered that the dysregulated sebum–microbial metabolite–IL-33 axis might play an initiating role in AD-related skin inflammation, thereby highlighting novel therapeutic strategies for the treatment of AD.

Aberrant RNA splicing in keratinocytes drives inflammatory skin disorders. In the present study, we found that the RNA helicase DDX5 was downregulated in keratinocytes from the inflammatory skin lesions in patients with atopic dermatitis and psoriasis, and that mice with keratinocyte-specific deletion of Ddx5 (Ddx5^∆KC) were more susceptible to cutaneous inflammation. Inhibition of DDX5 expression in keratinocytes was induced by the cytokine interleukin (IL)-17D through activation of the CD93–p38 MAPK–AKT–SMAD2/3 signaling pathway and led to pre-messenger RNA splicing events that favored the production of membrane-bound, intact IL-36 receptor (IL-36R) at the expense of soluble IL-36R (sIL-36R) and to the selective amplification of IL-36R-mediated inflammatory responses and cutaneous inflammation. Restoration of sIL-36R in Ddx5^∆KC mice with experimental atopic dermatitis or psoriasis suppressed skin inflammation and alleviated the disease phenotypes. These findings indicate that IL-17D modulation of DDX5 expression controls inflammation in keratinocytes during inflammatory skin diseases.