Abstract
cFLIP is required for epidermal integrity and skin inflammation silencing via protection from TNF-induced keratinocyte apoptosis. Here, we generated and analyzed cFLIP epidermal KO mice with additional TNF deficiency. Intriguingly, the ablation of TNF rescued the pathological phenotype of epidermal cFLIP KO from characteristic weight loss and increased mortality. Moreover, the lack of TNF in these animals strongly reduced and delayed the epidermal hyperkeratosis and the increased apoptosis in keratinocytes. Our data demonstrate that TNF signaling in cFLIP-deficient keratinocytes is the critical factor for the regulation of skin inflammation via modulated cytokine and chemokine expression and, thus, the attraction of immune cells. Our data suggest that autocrine TNF loop activation upon cFLIP deletion is dispensable for T cells, but is critical for neutrophil attraction. Our findings provide evidence for a negative regulatory role of cFLIP for TNF-dependent apoptosis and partially for epidermal inflammation. However, alternative signaling pathways may contribute to the development of the dramatic skin disease upon cFLIP deletion. Our data warrant future studies of the regulatory mechanism controlling the development of skin disease upon cFLIP deficiency and the role of cFLIP/TNF in a number of inflammatory skin diseases, including toxic epidermal necrolysis (TEN).
Highlights
Tumor necrosis factor (TNF) is a pleiotropic cytokine which is critical for retaining tissue homeostasis by controlling both cell death and inflammation
As a cFLIP-deficient skin strongly resembles the typical skin morphology of patients with toxic epidermal necrolysis (TEN), we previously suggested that cFLIP deficiency is a possible prerequisite for the fulminant cell death in the skin of TEN patients [7,10]
We could previously show the role of the TNF autocrine loop for the cell death induced in cFLIP-deficient keratinocytes in vivo [7]
Summary
Tumor necrosis factor (TNF) is a pleiotropic cytokine which is critical for retaining tissue homeostasis by controlling both cell death and inflammation. The first checkpoint is the TNF-R1 signaling complex (complex I), which forms upon TNF-R1 activation. The signaling mediated by this complex triggers the activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling, which results in the secretion of proinflammatory cytokines, including TNF [2]. TNF-R1 signaling can result in the formation and activation of secondary cytoplasmic complexes IIa and IIb (ripoptosome). Complexes II are formed upon interaction among RIPK1, adaptor protein FADD, caspase-8, and its protease deficient homolog cFLIP. Cleavage of caspase-8 on this platform results in the activation of apoptotic cell death. RIPK1 can directly interact with RIPK3, which activates necroptotic cell death. RIPK1 can directly interact with RIPK3, which activates necroptotic cell death. cFLIP has a critical role in the apoptosis or necroptosis decision within the ripoptosome [3]
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