Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages.
Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages.
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DOI：
10.1016/j.cub.2015.12.064
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发表时间：
2016-03-07
期刊：
影响因子：
--
通讯作者：
Bergmann A
中科院分区：
文献类型：
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作者：
Fogarty CE;Diwanji N;Lindblad JL;Tare M;Amcheslavsky A;Makhijani K;Brückner K;Fan Y;Bergmann A
细胞凋亡诱导的增殖（AiP）是正常发育过程中意外细胞损失后维持组织大小和形态的一种补偿机制，也可能是癌症和耐药性的一个促成因素。在凋亡细胞中，半胱天冬酶启动的信号级联导致下游促有丝分裂因子的产生和邻近存活细胞的增殖。在果蝇成虫盘的上皮细胞中，Caspase-9 直系同源物 Dronc 通过激活 Jun N 末端激酶 (JNK) 驱动 AiP；然而，JNK激活的具体机制仍不清楚。在这里，我们表明 AiP 期间 caspase 诱导的 JNK 激活取决于炎症反应。这是由上皮椎间盘细胞中 NADPH 氧化酶 Duox 产生的细胞外活性氧 (ROS) 介导的。细胞外 ROS 激活果蝇巨噬细胞（血细胞），巨噬细胞进而通过 TNF 直系同源物 Eiger 发出信号，触发上皮细胞中的 JNK 活性。我们提出，在 AiP 的永生化（“不死”）模型中，细胞外 ROS 和 TNF/Eiger 在上皮椎间盘细胞和血细胞之间来回传递信号，驱动椎间盘上皮过度生长。这些数据说明了双向细胞/细胞通讯途径，对组织修复、再生和癌症具有重要意义。
Apoptosis-induced proliferation (AiP) is a compensatory mechanism to maintain tissue size and morphology following unexpected cell loss during normal development, and may also be a contributing factor to cancer and drug resistance. In apoptotic cells, caspase-initiated signaling cascades lead to the downstream production of mitogenic factors and the proliferation of neighbouring surviving cells. In epithelial cells of Drosophila imaginal discs, the Caspase-9 ortholog Dronc drives AiP via activation of Jun N-terminal kinase (JNK); however, the specific mechanisms of JNK activation remain unknown. Here, we show that caspase-induced activation of JNK during AiP depends on an inflammatory response. This is mediated by extracellular reactive oxygen species (ROS) generated by the NADPH oxidase Duox in epithelial disc cells. Extracellular ROS activate Drosophila macrophages (hemocytes), which in turn trigger JNK activity in epithelial cells by signaling through the TNF ortholog Eiger. We propose that in an immortalized (‘undead’) model of AiP, signaling back and forth between epithelial disc cells and hemocytes by extracellular ROS and TNF/Eiger drives overgrowth of the disc epithelium. These data illustrate a bidirectional cell/cell communication pathway with implication for tissue repair, regeneration and cancer.