The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation

Immunity. 2011 Oct 28;35(4):572-82. doi: 10.1016/j.immuni.2011.08.014. Epub 2011 Oct 13.


Epidermal 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 (FADD(E-KO)) induced severe inflammatory skin lesions in mice. The development of skin inflammation in FADD(E-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cells, Cultured
  • Dermatitis / immunology*
  • Dermatitis / metabolism
  • Dermatitis / pathology*
  • Epidermis / immunology*
  • Fas-Associated Death Domain Protein / deficiency
  • Fas-Associated Death Domain Protein / immunology*
  • Homeostasis
  • Keratinocytes / immunology*
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / metabolism
  • Necrosis
  • Signal Transduction


  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88