The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair.
The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair.
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DOI：
10.1016/j.immuni.2014.09.016
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发表时间：
2014-10-16
期刊：
影响因子：
32.4
通讯作者：
Chan, Francis Ka-Ming
中科院分区：
文献类型：
--
作者：
Moriwaki, Kenta;Balaji, Sakthi;McQuade, Thomas;Malhotra, Nidhi;Kang, Joonsoo;Chan, Francis Ka-Ming
程序性坏死或坏死性下垂是细胞死亡的一种炎症性形式，严重需要受体相互作用蛋白激酶3(RIPK3)。在这里，我们证明了RIPK3通过调节树突状细胞(DC)细胞因子的表达来控制独立的、非坏死的炎症途径。RIPK3−/−骨髓来源的树突状细胞(BMDCs)在脂多糖诱导炎性细胞因子的表达方面存在严重缺陷。这些效应是由于NF-κB亚单位RelB和p50的激活以及半胱氨酸天冬氨酸蛋白酶1介导的白细胞介素1β(IL-1β)的处理受损所致。RIPK3的这种DC特异性功能对于损伤诱导的炎症和葡聚糖硫酸钠(DSS)反应的组织修复至关重要。RIPK3−/−小鼠表现出损伤诱导的IL-1β、IL-23和IL-22细胞因子级联反应的受损轴，这种损害可以通过过继转移野生型DC而部分纠正，但不能纠正RIPK3−/−树突状细胞。这些结果揭示了RIPK3在NF-κB激活、DC生物学、先天炎症细胞因子表达和损伤诱导的组织修复中意想不到的功能。
Programmed necrosis or necroptosis is an inflammatory form of cell death that critically requires the receptor interacting protein kinase 3 (RIPK3). Here we showed that RIPK3 controls a separate, necrosis-independent pathway of inflammation through regulating dendritic cells (DCs) cytokine expression. Ripk3−/− bone marrow derived dendritic cells (BMDCs) were highly defective in lipopolysaccharide (LPS)-induced expression of inflammatory cytokines. These effects were caused by impaired NF-κB subunit RelB and p50 activation and caspase 1-mediated processing of interleukin-1β (IL-1β). This DC-specific function of RIPK3 was critical for injury-induced inflammation and tissue repair in response to dextran sodium sulfate (DSS). Ripk3−/− mice exhibited an impaired axis of injury-induced IL-1β, IL-23 and IL-22 cytokine cascade, which was partially corrected by adoptive transfer of wild type DCs, but not Ripk3−/− DCs. These results reveal an unexpected function of RIPK3 in NF-κB activation, DC biology, innate inflammatory cytokine expression, and injury-induced tissue repair.
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