Department of Dermatology and Allergology, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.
Int J Mol Sci. 2020 Nov 23;21(22):8859. doi: 10.3390/ijms21228859.
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).
cFLIP 对于表皮完整性和皮肤炎症的抑制是必需的，可防止 TNF 诱导的角质形成细胞凋亡。在这里，我们生成并分析了具有额外 TNF 缺乏的表皮 cFLIP KO 小鼠。有趣的是，TNF 的缺失挽救了表皮 cFLIP KO 的病理性表型，使其特征性的体重减轻和死亡率增加得到改善。此外，这些动物中 TNF 的缺乏强烈减少并延迟了角质形成细胞的过度角化和增加的细胞凋亡。我们的数据表明，TNF 信号在 cFLIP 缺陷角质形成细胞中是通过调节细胞因子和趋化因子表达以及免疫细胞的吸引来调节皮肤炎症的关键因素。我们的数据表明，cFLIP 缺失后自分泌 TNF 循环激活对于 T 细胞不是必需的，但对于中性粒细胞的吸引是至关重要的。我们的发现为 cFLIP 依赖的细胞凋亡和部分表皮炎症的负调控作用提供了证据。然而，替代信号通路可能有助于 cFLIP 缺失后严重皮肤疾病的发展。我们的数据需要进一步研究控制 cFLIP 缺乏后皮肤疾病发展的调节机制，以及 cFLIP/TNF 在多种炎症性皮肤疾病中的作用，包括中毒性表皮坏死松解症（TEN）。
