cFLIP prevents TNFR1-dependent lethal dermatitis and TNFR1-independent blockade of epidermal differentiation. Mus musculus

Cellular FLICE-inhibitory protein (cFLIP) prevents the development of dermatitis by blocking TNFα-dependent apoptosis of keratinocytes. However, it is unclear whether TNFα-independent signal might also contribute to the development of dermatitis in epidermis-specific Cflar-deficient (Cflar) mice. Here we show that Cflar;Tnfrsf1a-/- mice were born at the expected Mendelian ratio, but developed severe dermatitis and succumbed soon after birth. While keratinocytes still died by apoptosis, expression of epidermal differentiation markers, such as Loricrin, Filaggrin, and Keratin (Krt)10, but not Krt5 were severely downregulated in the skin of Cflar;Tnfrsf1a-/- mice at both mRNA and protein levels. Conversely, inflammatory cytokines, such as interleukin (IL)-6 and Il17a were elevated in the skin of Cflar ;Tnfrsf1a-/- mice. Treatment of primary keratinocytes with IL-6, to a lesser extent IL-17A suppressed expression of Loricrin, Filaggrin, and Krt10. Together, cFLIP suppresses TNFR1-independent apoptosis of keratinocytes and prevents IL-6-dependent blockade of epidermal differentiation. Overall design: To identify the genes that might block epidermal differentiation and proliferation of keratinocytes, we compared gene expression of the skin between CflarF/F;Tnfrsf1a+/- and CflarF/F;K5-Cre;Tnfrsf1a+/- mice by microarray.