Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease.
Expression of enzymatically inactive caspase-8, or deletion of caspase-8 from basal epidermal keratinocytes, triggers chronic skin inflammation in mice. Unlike similar inflammation resulting from arrest of nuclear factor kappaB activation in the epidermal cells, the effect induced by caspase-8 deficiency did not depend on TNF, IL-1, dermal macrophage function, or expression of the toll-like receptor adapter proteins MyD88 or TRIF. Both interferon regulatory factor (IRF) 3 and TANK-binding kinase were constitutively phosphorylated in the caspase-8-deficient epidermis, and knockdown of IRF3 in the epidermis-derived cells from these mice abolished the expression of up-regulated genes. Temporal and spatial analyses of the alterations in gene expression that result from caspase-8 deficiency reveal that the changes are initiated before birth, around the time that cornification develops, and occur mainly in the suprabasal layer. Finally, we found that caspase-8-deficient keratinocytes display an enhanced response to gene activation by transfected DNA. Our findings suggest that an enhanced response to endogenous activators of IRF3 in the epidermis, presumably generated in association with keratinocyte differentiation, contributes to the skin inflammatory process triggered by caspase-8 deficiency.
Kovalenko
Andrew
A
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
Kim
Jin-Chul
JC
Kang
Tae-Bong
TB
Rajput
Akhil
A
Bogdanov
Konstantin
K
Dittrich-Breiholz
Oliver
O
Kracht
Michael
M
Brenner
Ori
O
Wallach
David
D
D056769:Alstrom Syndrome; D000818:Animals; D053181:Caspase 8 / Q000502:physiology*; D003872:Dermatitis / Q000209:etiology*; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000502:physiology; D015603:Keratinocytes / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012867:Skin / Q000473:pathology
D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; C505526:Casp8 protein, mouse; D053181:Caspase 8