Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation
Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation
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ZBP1对内源性核酸的感应诱导角质形成细胞坏死性凋亡和皮肤炎症
DOI：
10.1084/jem.20191913
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发表时间：
2020-07-01
影响因子：
15.3
通讯作者：
Maelfait, Jonathan
中科院分区：
文献类型：
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作者：
Devos, Michael;Tanghe, Giel;Maelfait, Jonathan
免疫系统对内源性核酸的异常检测可引起炎性疾病。信号传导激酶RIPK 1的支架功能限制了核酸传感器ZBP 1的自发激活。因此，角质形成细胞中RIPK 1的缺失诱导ZBP 1依赖性坏死性凋亡和皮肤炎症。在RIPK 1缺陷的情况下，是否需要核酸传感来激活ZBP 1，以及哪些免疫途径与皮肤病相关，仍然是悬而未决的问题。使用基因敲入小鼠与破坏ZBP 1核酸结合活性，我们报告说，感应内源性核酸的ZBP 1是至关重要的驱动皮肤病理特征的抗病毒和IL-17免疫反应。干扰素诱导ZBP 1表达触发RIPK 1缺陷型角质形成细胞的坏死性凋亡，MLKL的表皮特异性缺失可预防疾病，表明细胞内在事件引起炎症。这些发现表明，ZBP 1对内源性核酸的传感失调可以驱动炎症，并可能导致IL-17驱动的炎症性皮肤病如银屑病的发病机制。
Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signaling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1-deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid-binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterized by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes, and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17-driven inflammatory skin conditions such as psoriasis.