RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex.
RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex.
复制标题
DOI：
10.1093/cercor/bhy089
复制
发表时间：
2018-07-01
期刊：
影响因子：
--
通讯作者：
Wu S
中科院分区：
文献类型：
--
作者：
Yang J;Zhao Y;Zhang L;Fan H;Qi C;Zhang K;Liu X;Fei L;Chen S;Wang M;Kuang F;Wang Y;Wu S
细胞死亡和随后的炎症是脑缺血发生的2个关键病理变化。活跃的小胶质细胞/巨噬细胞根据其M1/M2表型的平衡发挥双刃作用。坏死是缺血后细胞死亡的主要类型。然而，坏死细胞如何调节小胶质细胞/巨噬细胞的M1/M2极化仍然很少研究。在这里，我们报道了缺血诱导快速RIPK 3/MLKL介导的神经元主导的坏死性凋亡，一种程序性坏死。表达RIPK 3或MLKL可使缺血皮质中小胶质细胞/巨噬细胞的活化从M1型转变为M2型。氧-葡萄糖剥夺（OGD）处理的野生型（WT）神经元的条件培养基诱导M1极化，而RIPK 3 −/−神经元的条件培养基有利于M2极化。OGD处理在WT中诱导促炎性IL-18和TNFα，但在RIPK 3 −/−神经元中不诱导，这反过来上调抗炎性IL-4和IL-10。此外，Myd 88-toll样受体的常见下游衔接子-的表达在缺血WT的小胶质细胞/巨噬细胞中显著上调，但在RIPK 3 −/−或MLKL−/−皮质中没有。拮抗Myd 88的功能可以表型复制RIPK 3/MLKL敲除对小胶质细胞/巨噬细胞极化的影响，并且具有神经保护作用。我们的数据揭示了坏死性神经元在调节缺血皮质中小胶质细胞/巨噬细胞的M1/M2平衡中的新作用，可能通过Myd 88信号传导。
Cell death and subsequent inflammation are 2 key pathological changes occurring in cerebral ischemia. Active microglia/macrophages play a double-edged role depending on the balance of their M1/M2 phenotypes. Necrosis is the predominant type of cell death following ischemia. However, how necrotic cells modulate the M1/M2 polarization of microglia/macrophages remains poorly investigated. Here, we reported that ischemia induces a rapid RIPK3/MLKL-mediated neuron-dominated necroptosis, a type of programmed necrosis. Ablating RIPK3 or MLKL could switch the activation of microglia/macrophages from M1 to the M2 type in the ischemic cortex. Conditioned medium of oxygen-glucose deprivation (OGD)-treated wild-type (WT) neurons induced M1 polarization, while that of RIPK3−/− neurons favored M2 polarization. OGD treatment induces proinflammatory IL-18 and TNFα in WT but not in RIPK3−/− neurons, which in turn upregulate anti-inflammatory IL-4 and IL-10. Furthermore, the expression of Myd88—a common downstream adaptor of toll-like receptors—is significantly upregulated in the microglia/macrophages of ischemic WT but not of RIPK3−/− or MLKL−/− cortices. Antagonizing the function of Myd88 could phenocopy the effects of RIPK3/MLKL-knockout on the polarization of microglia/macrophages and was neuroprotective. Our data revealed a novel role of necroptotic neurons in modulating the M1/M2 balance of microglia/macrophages in the ischemic cortex, possibly through Myd88 signaling.
登录
查看更多内容
小胶质细胞坏死性凋亡通过 TLR4 激活导致神经炎症和视网膜变性
影响因子：
12.4
作者：
Huang Z;Zhou T;Sun X;Zheng Y;Cheng B;Li M;Liu X;He C
通讯作者：
He C
影响因子：
6.3
作者：
Brea, David;Blanco, Miguel;Castillo, Jose
通讯作者：
Castillo, Jose
影响因子：
--
作者：
Lee, Jung-Kil;Park, Min-Sung;Kim, Soo-Han
通讯作者：
Kim, Soo-Han
在细胞死亡和炎症的串扰中进行了编程坏死。
影响因子：
29.7
作者：
Chan FK;Luz NF;Moriwaki K
通讯作者：
Moriwaki K
Interleukin-4 对于小胶质细胞/巨噬细胞 M2 极化和脑缺血后的长期恢复至关重要
影响因子：
8.3
作者：
Liu X;Liu J;Zhao S;Zhang H;Cai W;Cai M;Ji X;Leak RK;Gao Y;Chen J;Hu X
通讯作者：
Hu X