The Critical Role of Proteolytic Relay through Cathepsins B and E in the Phenotypic Change of Microglia/Macrophage
The Critical Role of Proteolytic Relay through Cathepsins B and E in the Phenotypic Change of Microglia/Macrophage
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DOI：
10.1523/jneurosci.1599-15.2015
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发表时间：
2015-09-09
影响因子：
5.3
通讯作者：
Nakanishi, Hiroshi
中科院分区：
文献类型：
--
作者：
Ni, Junjun;Wu, Zhou;Nakanishi, Hiroshi
蛋白酶级联反应是神经元死亡途径基本机制的一部分。神经元组织蛋白酶B （CatB）是一种典型的半胱氨酸溶酶体蛋白酶，通过溶酶体渗漏或过度自噬在神经元死亡中起关键作用。另一方面，小胶质细胞CatB在神经元死亡中的作用也受到了广泛的关注。本研究表明，在神经毒性表型中，小胶质细胞/巨噬细胞极化导致缺氧/缺血（HI）诱导的新生小鼠海马神经元损伤中，通过小胶质细胞CatB和CatE的蛋白水解接力发挥了关键作用。HI在新生野生型小鼠中引起广泛的脑损伤，但在CatB（-/-）小鼠中没有。此外，在野生型小鼠中，hi诱导的小胶质细胞/巨噬细胞极化先是神经毒性表型，然后是神经保护表型。另一方面，在CatB（-/-）小鼠中，小胶质细胞/巨噬细胞仅表现出早期和短暂的神经保护表型极化。CA-074Me是一种特异性的CatB抑制剂，可显著抑制神经毒性表型培养小胶质细胞极化条件培养基诱导的原代培养海马神经元的神经元死亡。此外，CA-074Me通过抑制氧-葡萄糖剥夺后kappa B α降解的自噬抑制剂，阻止了培养小胶质细胞中核因子- κ B （nf - κ B）的活化。令人惊讶的是，通过蛋白酶体途径从小胶质细胞中释放肿瘤坏死因子相关的凋亡诱导配体（TRAIL）， CatE增加了HI后CatB的表达。HI后，仅在小胶质细胞/巨噬细胞中发现CatB和CatE水平显著升高。因此，NF-kappa B激活的早期依赖于CatE/ trail的蛋白体和晚期依赖于catb的自噬途径的蛋白水解中继可能在神经毒性表型中小胶质细胞/巨噬细胞的极化中发挥关键作用。
Proteinase cascades are part of the basic machinery of neuronal death pathways. Neuronal cathepsin B (CatB), a typical cysteine lysosomal protease, plays a critical role in neuronal death through lysosomal leakage or excessive autophagy. On the other hand, much attention has been paid to microglial CatB in neuronal death. Weherein show the critical role of proteolytic relay through microglial CatB and CatE in the polarization of microglia/macrophages in the neurotoxic phenotype, leading to hypoxia/ischemia (HI)-induced hippocampal neuronal damage in neonatal mice. HI caused extensive brain injury in neonatal wild-type mice, but not in CatB(-/-) mice. Furthermore, HI-induced polarization of microglia/macrophages in the neurotoxic phenotype followed by the neuroprotective phenotype in wild-type mice. On the other hand, microglia/macrophages exhibited only the early and transient polarization in the neuroprotective phenotype in CatB(-/-) mice. CA-074Me, a specific CatB inhibitor, significantly inhibited the neuronal death of primary cultured hippocampal neurons induced by the conditionedmediumfrom cultured microglia polarized in the neurotoxic phenotype. Furthermore, CA-074Me prevented the activation of nuclear factor-kappa B (NF-kappa B) in cultured microglia by inhibiting autophagic inhibitor of kappa B alpha degradation following exposure to oxygen-glucose deprivation. Rather surprisingly, CatE increased the CatB expression after HI by the liberation of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) from microglia through the proteasomal pathway. A significant increase in CatB and CatE levels was found exclusively in microglia/macrophages after HI. Thus, a proteolytic relay through the early CatE/TRAIL-dependent proteosomal and late CatB-dependent autophagic pathways for NF-kappa B activation may play a critical role in the polarization of microglia/macrophages in the neurotoxic phenotype.