Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 36, Pages 12488-12501Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1599-15.2015
Keywords
autophagy; cathepsin B; cathepsin E; hypoxic ischemia; microglia; phenotypic change
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Funding
- Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development
- Grants-in-Aid for Scientific Research [15H05015, 15K15684] Funding Source: KAKEN
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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.
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