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 language | English |
|---|---|
| Pages (from-to) | 12488-12501 |
| Number of pages | 14 |
| Journal | Journal of Neuroscience |
| Volume | 35 |
| Issue number | 36 |
| DOIs | |
| Publication status | Published - Sep 9 2015 |
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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 journal › Article
}
TY - JOUR
T1 - The critical role of proteolytic relay through cathepsins B and E in the phenotypic change of microglia/macrophage
AU - Ni, Junjun
AU - Take, Hiro
AU - Peterts, Christoph
AU - Yamamoto, Kenji
AU - Qing, Hong
AU - Nakanishi, Hiroshi
PY - 2015/9/9
Y1 - 2015/9/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84941241689&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84941241689&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1599-15.2015
DO - 10.1523/JNEUROSCI.1599-15.2015
M3 - Article
VL - 35
SP - 12488
EP - 12501
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 36
ER -