PPARα deficiency causes skin dysbiosis and triggers innate immunity in keratinocytes.

Peroxisome proliferator-activated receptor-α (PPARα) is a transcription factor expressed in the skin, where its physiological role remains largely unknown. In this work, we found decreased bacterial density and dysbiosis associated with reduced amounts of Staphylococcus in the skin of PPARα-deficient mice compared to littermate controls. The NOD2 pathway was enhanced, as shown by up-regulation of both NOD2 and its downstream targets, including the antimicrobial peptides mBD3 and mBD4. Moreover, the Th17 immune response was enhanced in keratinocytes and epidermal dendritic T cells. Topical treatment of PPARα-deficient mice with an antibacterial solution did not normalize the upregulation of the innate immunity in keratinocytes. However, the up-regulation of FLG and excessive oxidative stress detected in the epidermis of PPARα-deficient mice were markedly inhibited by topical antibacterial treatment. Thus, our study highlights the overarching role of PPARα in shaping skin immune system and microbiota, with the latter largely controlling FLG expression and inducing oxidative stress in keratinocytes.