RRC ID 37925
著者 Ni J, Wu Z, Peterts C, Yamamoto K, Qing H, Nakanishi H.
タイトル The Critical Role of Proteolytic Relay through Cathepsins B and E in the Phenotypic Change of Microglia/Macrophage.
ジャーナル J Neurosci
Abstract 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. We herein 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 conditioned medium from cultured microglia polarized in the neurotoxic phenotype. Furthermore, CA-074Me prevented the activation of nuclear factor-κB (NF-κB) in cultured microglia by inhibiting autophagic inhibitor of κBα 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-κB activation may play a critical role in the polarization of microglia/macrophages in the neurotoxic phenotype. Significance statement: Proteinase cascades are part of the basic machinery of neuronal death pathways. Cathepsin B, a typical cysteine lysosomal protease, plays a critical role in neuronal death through lysosomal leakage or excessive autophagy in neurons. On the other hand, much attention has been also paid to the role of microglial cathepsin B in neuronal death. In this study, using in vivo and in vitro models of relevance to brain ischemia, we found a critical role of proteolytic relay through cathepsin B and cathepsin E in the neurotoxic polarization of microglia/macrophages, which is responsible for aggravation of hypoxia/ischemia-induced neuronal injury. These findings suggest orally active selective inhibitors of cathepsin B or cathepsin E as promising pharmacological agents for the treatment of ischemic brain injury.
巻・号 35(36)
ページ 12488-501
公開日 2015-9-9
DOI 10.1523/JNEUROSCI.1599-15.2015
PII 35/36/12488
PMID 26354916
PMC PMC6605404
MeSH Animals Cathepsin B / antagonists & inhibitors Cathepsin B / genetics Cathepsin B / metabolism* Cathepsin E / genetics Cathepsin E / metabolism* Cells, Cultured Dipeptides / pharmacology Hippocampus / metabolism Hypoxia-Ischemia, Brain / metabolism* Macrophages / drug effects Macrophages / metabolism* Mice Mice, Inbred C57BL Microglia / drug effects Microglia / metabolism* NF-kappa B / metabolism Neurons / drug effects Neuroprotective Agents / pharmacology Phenotype Protease Inhibitors / pharmacology Proteolysis* Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
IF 5.674
引用数 31
WOS 分野 NEUROSCIENCES
リソース情報
ヒト・動物細胞 MG6(RCB2403)