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Inhibition of cathepsin X reduces the strength of microglial-mediated neuroinflammation.

Abstract：

:Inflammation plays a central role in the processes associated with neurodegeneration. The inflammatory response is mediated by activated microglia that release inflammatory mediators to the neuronal environment. Microglia-derived lysosomal cathepsins, including cathepsin X, are increasingly recognized as important mediators of the inflammation involved in lipopolysaccharide (LPS)-induced neuroinflammation. The current study was undertaken to investigate the role of cathepsin X and its molecular target, γ-enolase, in neuroinflammation and to elucidate the underlying mechanism. We determined that the exposure of activated BV2 and EOC 13.31 cells to LPS led to increased levels of cathepsin X protein and activity in the culture supernatants in a concentration- and time-dependent manner. In contrast, LPS stimulation of these two cells reduced the release of active γ-enolase in a manner regulated by the cathepsin X activity. Cathepsin X inhibitor AMS36 significantly reduced LPS-induced production of nitric oxide, reactive oxygen species and the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α from BV2 cells. Inhibition of cathepsin X suppressed microglial activation through the reduced caspase-3 activity, together with diminished microglial cell death and apoptosis, and also through inhibition of the activity of the mitogen-activated protein kinases. Further, SH-SY5Y treatment with culture supernatants of activated microglial cells showed that cathepsin X inhibition reduces microglia-mediated neurotoxicity. These results indicate that up-regulated expression and increased release and activity of microglial cathepsin X leads to microglia activation-mediated neurodegeneration. Cathepsin X inhibitor caused neuroprotection via its inhibition of the activation of microglia. Cathepsin X could thus be a potential therapeutic target for neuroinflammatory disorders.

journal_name

Neuropharmacology

journal_title

Neuropharmacology

authors

Pišlar A,Božić B,Zidar N,Kos J

doi

10.1016/j.neuropharm.2016.11.019

subject

Has Abstract

pub_date

2017-03-01 00:00:00

pages

88-100

eissn

0028-3908

issn

1873-7064

pii

S0028-3908(16)30523-8

journal_volume

114

pub_type

杂志文章

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Inhibition of cathepsin X reduces the strength of microglial-mediated neuroinflammation.