The Adaptor Protein FADD Protects Epidermal Keratinocytes from Necroptosis In Vivo and Prevents Skin Inflammation

SummaryEpidermal keratinocytes provide an essential structural and immunological barrier forming the first line of defense against potentially pathogenic microorganisms. Mechanisms regulating barrier integrity and innate immune responses in the epidermis are important for the maintenance of skin immune homeostasis and the pathogenesis of inflammatory skin diseases. Here, we show that epidermal keratinocyte-restricted deficiency of the adaptor protein FADD (FADDE-KO) induced severe inflammatory skin lesions in mice. The development of skin inflammation in FADDE-KO mice was triggered by RIP kinase 3 (RIP3)-mediated programmed necrosis (termed necroptosis) of FADD-deficient keratinocytes, which was partly dependent on the deubiquitinating enzyme CYLD and tumor necrosis factor (TNF)-TNF receptor 1 signaling. Collectively, our findings provide an in vivo experimental paradigm that regulation of necroptosis in keratinocytes is important for the maintenance of immune homeostasis and the prevention of chronic inflammation in the skin.

Graphical AbstractFigure optionsDownload high-quality image (167 K)Download as PowerPoint slideHighlights
► Epidermal FADD deficiency triggers keratinocyte necrosis and skin inflammation in mice
► RIP3-mediated keratinocyte necroptosis triggers skin inflammation in FADDEKO mice
► Keratinocyte necrosis and inflammation in FADDEKO mice partly depend on CYLD and TNFR
► MyD88 signaling contributes to skin inflammation in FADDEKO mice