Reactive astrocytes undergo M1 microglia/macrohpages- induced necroptosis in spinal cord injury
Reactive astrocytes undergo M1 microglia/macrohpages- induced necroptosis in spinal cord injury
复制标题
脊髓损伤中反应性星形胶质细胞经历 M1 小胶质细胞/巨噬细胞诱导的坏死性凋亡
DOI：
10.1186/s13024-016-0081-8
复制
发表时间：
2016-02-03
影响因子：
15.1
通讯作者：
Wang, Ya-Zhou
中科院分区：
文献类型：
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作者：
Fan, Hong;Zhang, Kun;Wang, Ya-Zhou
脊髓损伤后病理改变的一个独特特征是病变面积进行性扩大，通常导致空洞形成，并伴有反应性星形胶质细胞增生和慢性炎症。反应性星形胶质细胞排列在脊髓腔内，将病变中心与正常脊髓组织隔开，被认为在脊髓损伤中发挥着多种重要作用。空化过程中细胞死亡的贡献，特别是神经元和少突胶质细胞的凋亡已被广泛研究。然而，脊髓损伤后反应性星形胶质细胞是如何被清除的，目前尚不清楚。结果通过免疫组织化学方法，在PI标记和电子显微镜检查中，我们报道了在小鼠中，反应性星形胶质细胞是由受体相互作用蛋白3和混合谱系激酶区样蛋白(RIP3/MLKL)介导的坏死性下垂引起的，而不是凋亡或自噬。抑制受体相互作用蛋白1(RIP1)或耗尽RIP3不仅可以显著减轻星形胶质细胞的死亡，而且可以恢复星形胶质细胞的神经营养功能。脊髓损伤后，星形胶质细胞表达的坏死性标志物遵循M1小胶质细胞/巨噬细胞的极化。去除M1小胶质细胞/巨噬细胞或移植M1巨噬细胞可明显减轻或增加星形胶质细胞的坏死性下垂。此外，炎症反应基因Toll样受体4(TLR4)和髓系分化初级反应基因88(MyD88)在坏死性星形胶质细胞中被诱导，在体外拮抗星形胶质细胞中的MyD88可以显著减轻M1小胶质/巨噬细胞诱导的细胞死亡。结论脊髓损伤后，反应性星形胶质细胞发生M1小胶质细胞/巨噬细胞诱导的坏死性下垂，部分通过TLR/MyD88信号转导，抑制星形胶质细胞坏死性下垂可能有助于预防继发性脊髓损伤。
BackgroundA unique feature of the pathological change after spinal cord injury (SCI) is the progressive enlargement of lesion area, which usually results in cavity formation and is accompanied by reactive astrogliosis and chronic inflammation. Reactive astrocytes line the spinal cavity, walling off the lesion core from the normal spinal tissue, and are thought to play multiple important roles in SCI. The contribution of cell death, particularly the apoptosis of neurons and oligodendrocytes during the process of cavitation has been extensively studied. However, how reactive astrocytes are eliminated following SCI remains largely unclear.ResultsBy immunohistochemistry,in vivopropidium iodide (PI)-labeling and electron microscopic examination, here we reported that in mice, reactive astrocytes died by receptor-interacting protein 3 and mixed lineage kinase domain-like protein (RIP3/MLKL) mediated necroptosis, rather than apoptosis or autophagy. Inhibiting receptor-interacting protein 1 (RIP1) or depleting RIP3 not only significantly attenuated astrocyte death but also rescued the neurotrophic function of astrocytes. The astrocytic expression of necroptotic markers followed the polarization of M1 microglia/macrophages after SCI. Depleting M1 microglia/macrophages or transplantation of M1 macrophages could significantly reduce or increase the necroptosis of astrocytes. Further, the inflammatory responsive genes Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) are induced in necroptotic astrocytes.In vitroantagonizing MyD88 in astrocytes could significantly alleviate the M1 microglia/macrophages-induced cell death. Finally, our data showed that in human, necroptotic markers and TLR4/MyD88 were co-expressed in astrocytes of injured, but not normal spinal cord.ConclusionTaken together, these results reveal that after SCI, reactive astrocytes undergo M1 microglia/macrophages-induced necroptosis, partially through TLR/MyD88 signaling, and suggest that inhibiting astrocytic necroptosis may be beneficial for preventing secondary SCI.