The critical role of proteolytic relay through cathepsins B and E in the phenotypic change of microglia/macrophage

Junjun Ni, Hiro Take, Christoph Peterts, Kenji Yamamoto, Hong Qing, Hiroshi Nakanishi

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.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-kB (NF-kB) in cultured microglia by inhibiting autophagic inhibitor of kBa 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-kB activation may play a critical role in the polarization of microglia/macrophages in the neurotoxic phenotype.

Original languageEnglish
Pages (from-to)12488-12501
Number of pages14
JournalJournal of Neuroscience
Volume35
Issue number36
DOIs
Publication statusPublished - Sep 9 2015

Fingerprint

Cathepsin E
Cathepsin B
Microglia
Macrophages
Phenotype
Ischemia
Cysteine Proteases
Autophagy
Brain Injuries
Peptide Hydrolases
Tumor Necrosis Factor-alpha

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

The critical role of proteolytic relay through cathepsins B and E in the phenotypic change of microglia/macrophage. / Ni, Junjun; Take, Hiro; Peterts, Christoph; Yamamoto, Kenji; Qing, Hong; Nakanishi, Hiroshi.

In: Journal of Neuroscience, Vol. 35, No. 36, 09.09.2015, p. 12488-12501.

Research output: Contribution to journalArticle

Ni, Junjun ; Take, Hiro ; Peterts, Christoph ; Yamamoto, Kenji ; Qing, Hong ; Nakanishi, Hiroshi. / The critical role of proteolytic relay through cathepsins B and E in the phenotypic change of microglia/macrophage. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 36. pp. 12488-12501.
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