The Potential of Therapeutic Targeting of the TWEAK-Fn14 pathway in Atopic Dermatitis

Abstract Atopic dermatitis (AD) is a chronic skin inflammatory condition exhibiting a markedly thickened epidermis. Keratinocytes, the major cells of the epidermis, are a key target of inflammation and several cytokines including IL-13 and IL-22 have receptors expressed on these cells. Because Fn14 (TNFRSF12A), the receptor for the TNF family cytokine TWEAK (TNFSF12), is also expressed on keratinocytes, we examined the inflammatory potential of TWEAK alone, and together with IL-13 and IL-22, in controlling AD-signature gene expression in using RNA-seq. Transcriptomic analysis showed that TWEAK strongly upregulated many AD genes in human keratinocytes, which partially overlapped with those induced by IL-13 and IL-22. TWEAK also acted synergistically with IL-13 and IL-22 to exaggerate induction of AD-related genes. Correspondingly, cKO mice lacking Fn14 only in keratinocytes were protected from developing pronounced allergen-induced AD-like skin inflammation. Furthermore, mice treated therapeutically with anti-TWEAK exhibited a significantly reduced AD phenotype including less epidermal thickening combined with a strongly reduced Th2 response in the skin. Moreover, the therapeutic efficacy of TWEAK inhibition was similar to that resulting from blockade of IL-13. The data suggest that TWEAK shares pathogenic activity with IL-13 and IL-22 and can be considered as a potential therapeutic target in AD similar to IL-13. Nil