(A) In normal wild-type skin TNF signalling might be activated by local penetration of bacteria into the epidermis. This will induce TNF, presumably by keratinocytes themselves or other resident cells such as Langerhans cells, and promotes canonical NF-κB signalling, inflammatory cytokine production and expression of prosurvival genes. If this response nullifies the threat, TNF signalling is turned off and homeostasis of the skin is maintained. (B) In the absence of TRAF2 in keratinocytes, TNF production can induce apoptotic cell death. This cell death, possibly because of the release of DAMPs, recruits neutrophils and other inflammatory cells to the skin and causes epidermal hyperplasia. Loss of TRAF2 also causes constitutive non-canonical NF-κB activation in viable keratinocytes, which increases the production and release of inflammatory cytokines, including TNF. Thus, TRAF2-deficient keratinocytes do not need to be stimulated by bacteria to produce TNF, and TNF-induced death sets up a potentially vicious cycle of inflammation. (C) Concomitant deletion of Tnf in mice with Traf2-deficient keratinocytes breaks this vicious cycle and prevents apoptosis of keratinocytes and early onset of the psoriasis-like phenotype. (D) In the absence of TNF, Traf2-deficient keratinocytes still produce inflammatory cytokines via the non-canonical NF-κB pathway that ultimately generate the same psoriasis-like phenotype in mice but with slower onset. These cytokines recruit inflammatory immune cells to the skin, including neutrophils and IFNγ+ T cells.