title: The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation.
abstract: 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.
authors: Institute for Genetics, Center for Molecular Medicine, and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany.
authors: Marion C
authors: MC
authors: Bonnet
authors: Daniela
authors: D
authors: Preukschat
authors: Patrick-Simon
authors: PS
authors: Welz
authors: Geert
authors: G
authors: van Loo
authors: Maria A
authors: MA
authors: Ermolaeva
authors: Wilhelm
authors: W
authors: Bloch
authors: Ingo
authors: I
authors: Haase
authors: Manolis
authors: M
authors: Pasparakis
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003872:Dermatitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D004817:Epidermis / Q000276:immunology*; D053200:Fas-Associated Death Domain Protein / Q000172:deficiency / Q000276:immunology*; D006706:Homeostasis; D015603:Keratinocytes / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009336:Necrosis; D015398:Signal Transduction
chemical_list: C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88