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The induction of neuronal death by up-regulated microglial cathepsin H in LPS-induced neuroinflammation.

Fan K, Li D, Zhang Y, Han C, Liang J, Hou C, Xiao H, Ikenaka K, Ma J - J Neuroinflammation (2015)

Bottom Line: Twenty-four hours after LPS injection, Cat H mRNA expression was maximal in SNr; 72 h later, it peaked in cerebral cortex and hippocampus then decreased and maintained at a low level.Taken together, these data indicate that the up-regulated microglial Cat H expression, release, and activity in the brain lead to neuronal death in neuroinflammation.The functional link of Cat H with microglial activation might contribute to the initiation and maintenance of microglia-driven chronic neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Dalian Medical University, West Section No. 9, South Road, Lvshun, Dalian, 116044, , Liaoning, China. fankaijunjun@hotmail.com.

ABSTRACT

Background: Neuroinflammation is a hallmark that leads to selective neuronal loss and/or dysfunction in neurodegenerative disorders. Microglia-derived lysosomal cathepsins are increasingly recognized as important inflammatory mediators to trigger signaling pathways that aggravate neuroinflammation. However, cathepsin H (Cat H), a cysteine protease, has been far less studied in neuroinflammation, compared to cathepsins B, D, L, and S. The expression patterns and functional roles of Cat H in the brain in neuroinflammation remain unknown.

Methods: C57BL/6J mice were intraperitoneally injected with either 0.9% saline or lipopolysaccharide (LPS, 5 mg/kg). Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to analyze expression and localization of Cat H in the brain. Nitrite assay was used to examine microglial activation in vitro; ELISA was used to determine the release of Cat H and proinflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ). Cat H activity was analyzed by cellular Cat H assay kit. Flow cytometry and in situ cell death detection were used to investigate neuronal death. Data were evaluated for statistical significance with one-way ANOVA and t test.

Results: Cat H mRNA was only present in perivascular microglia and non-parenchymal sites under normal conditions. After LPS injection, Cat H mRNA expression in activated microglia in different brain regions was increased. Twenty-four hours after LPS injection, Cat H mRNA expression was maximal in SNr; 72 h later, it peaked in cerebral cortex and hippocampus then decreased and maintained at a low level. The expression of Cat H protein exhibited the similar alterations after LPS injection. In vitro, inflammatory stimulation (LPS, TNF-α, IL-1β, IL-6, and IFN-γ) increased the release and activity of Cat H in microglia. Conversely, addition of Cat H to microglia promoted the production and release of NO, IL-1β, and IFN-γ which could be prevented by neutralizing antibody. Further, addition of Cat H to Neuro2a cells induced neuronal death.

Conclusions: Taken together, these data indicate that the up-regulated microglial Cat H expression, release, and activity in the brain lead to neuronal death in neuroinflammation. The functional link of Cat H with microglial activation might contribute to the initiation and maintenance of microglia-driven chronic neuroinflammation.

No MeSH data available.


Related in: MedlinePlus

The function link of Cat H with microglia activation inducing neuronal apoptosis. Inflammatory cytokines induced Cat H release from microglia and enhanced its activity. Also, Cat H induced microglial activation characterized by the release of inflammatory cytokines. Cat H, alone or in combination of inflammatory cytokines, contributes to neuronal apoptosis.
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Fig6: The function link of Cat H with microglia activation inducing neuronal apoptosis. Inflammatory cytokines induced Cat H release from microglia and enhanced its activity. Also, Cat H induced microglial activation characterized by the release of inflammatory cytokines. Cat H, alone or in combination of inflammatory cytokines, contributes to neuronal apoptosis.

Mentions: On the other hand, active Cat H induced microglial activation characterized by the release of NO and various proinflammatory cytokines. More importantly, active Cat H was toxic to neurons and induced neuronal death. These findings lead us to a hypothesis that the functional link of Cat H with microglia activation might involve a self-sustaining amplifying circle, contributing to the initiation and maintenance of microglia-driven chronic inflammation (Figure 6). To the best of our knowledge, this is the first report to reveal the regional expression and cellular localization of Cat H in the brain and highlight its potentially functional role in neuroinflammation.Figure 6


The induction of neuronal death by up-regulated microglial cathepsin H in LPS-induced neuroinflammation.

Fan K, Li D, Zhang Y, Han C, Liang J, Hou C, Xiao H, Ikenaka K, Ma J - J Neuroinflammation (2015)

The function link of Cat H with microglia activation inducing neuronal apoptosis. Inflammatory cytokines induced Cat H release from microglia and enhanced its activity. Also, Cat H induced microglial activation characterized by the release of inflammatory cytokines. Cat H, alone or in combination of inflammatory cytokines, contributes to neuronal apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4379721&req=5

Fig6: The function link of Cat H with microglia activation inducing neuronal apoptosis. Inflammatory cytokines induced Cat H release from microglia and enhanced its activity. Also, Cat H induced microglial activation characterized by the release of inflammatory cytokines. Cat H, alone or in combination of inflammatory cytokines, contributes to neuronal apoptosis.
Mentions: On the other hand, active Cat H induced microglial activation characterized by the release of NO and various proinflammatory cytokines. More importantly, active Cat H was toxic to neurons and induced neuronal death. These findings lead us to a hypothesis that the functional link of Cat H with microglia activation might involve a self-sustaining amplifying circle, contributing to the initiation and maintenance of microglia-driven chronic inflammation (Figure 6). To the best of our knowledge, this is the first report to reveal the regional expression and cellular localization of Cat H in the brain and highlight its potentially functional role in neuroinflammation.Figure 6

Bottom Line: Twenty-four hours after LPS injection, Cat H mRNA expression was maximal in SNr; 72 h later, it peaked in cerebral cortex and hippocampus then decreased and maintained at a low level.Taken together, these data indicate that the up-regulated microglial Cat H expression, release, and activity in the brain lead to neuronal death in neuroinflammation.The functional link of Cat H with microglial activation might contribute to the initiation and maintenance of microglia-driven chronic neuroinflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Dalian Medical University, West Section No. 9, South Road, Lvshun, Dalian, 116044, , Liaoning, China. fankaijunjun@hotmail.com.

ABSTRACT

Background: Neuroinflammation is a hallmark that leads to selective neuronal loss and/or dysfunction in neurodegenerative disorders. Microglia-derived lysosomal cathepsins are increasingly recognized as important inflammatory mediators to trigger signaling pathways that aggravate neuroinflammation. However, cathepsin H (Cat H), a cysteine protease, has been far less studied in neuroinflammation, compared to cathepsins B, D, L, and S. The expression patterns and functional roles of Cat H in the brain in neuroinflammation remain unknown.

Methods: C57BL/6J mice were intraperitoneally injected with either 0.9% saline or lipopolysaccharide (LPS, 5 mg/kg). Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to analyze expression and localization of Cat H in the brain. Nitrite assay was used to examine microglial activation in vitro; ELISA was used to determine the release of Cat H and proinflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ). Cat H activity was analyzed by cellular Cat H assay kit. Flow cytometry and in situ cell death detection were used to investigate neuronal death. Data were evaluated for statistical significance with one-way ANOVA and t test.

Results: Cat H mRNA was only present in perivascular microglia and non-parenchymal sites under normal conditions. After LPS injection, Cat H mRNA expression in activated microglia in different brain regions was increased. Twenty-four hours after LPS injection, Cat H mRNA expression was maximal in SNr; 72 h later, it peaked in cerebral cortex and hippocampus then decreased and maintained at a low level. The expression of Cat H protein exhibited the similar alterations after LPS injection. In vitro, inflammatory stimulation (LPS, TNF-α, IL-1β, IL-6, and IFN-γ) increased the release and activity of Cat H in microglia. Conversely, addition of Cat H to microglia promoted the production and release of NO, IL-1β, and IFN-γ which could be prevented by neutralizing antibody. Further, addition of Cat H to Neuro2a cells induced neuronal death.

Conclusions: Taken together, these data indicate that the up-regulated microglial Cat H expression, release, and activity in the brain lead to neuronal death in neuroinflammation. The functional link of Cat H with microglial activation might contribute to the initiation and maintenance of microglia-driven chronic neuroinflammation.

No MeSH data available.


Related in: MedlinePlus