Neuroinflammation-Induced Upregulation of Glial Cathepsin X Expression and Activity in vivo

Abstract

Neuroinflammation is an important factor in the pathogenesis of neurodegenerative diseases. Microglia-derived lysosomal cathepsins have been increasingly recognized as important inflammatory mediators that trigger signaling pathways that aggravate neuroinflammation. In vitro, a contribution to neuroinflammation processes has been shown for cathepsin X: however, the expression patterns and functional role of cathepsin X in neuroinflammatory brain pathology remain elusive. In this study we analyzed the expression, activity, regional distribution and cellular localization of cathepsin X in the rat brain with neuroinflammation-induced neurodegeneration. The unilateral injection of lipopolysaccharide (LPS) induced a strong upregulation of cathepsin X expression and its activity in the ipsilateral striatum. In addition to the striatum, cathepsin X overexpression was detected in other brain areas such as the cerebral cortex, corpus callosum, subventricular zone and external globus pallidus, whereas the upregulation was mainly restricted to activated microglia and reactive astrocytes. Continuous administration of the cathepsin X inhibitor AMS36 indicated protective effects against LPS-induced striatal degeneration, as seen by the attenuated LPS-mediated dilation of the lateral ventricles and partial decreased extent of striatal lesion. Taken together, our results indicate that cathepsin X plays a role as a pathogenic factor in neuroinflammation-induced neurodegeneration and represents a potential therapeutic target for neurodegenerative diseases associated with neuroinflammation.

Proteomics and bioinformatics reveal insights into neuroinflammation in the acute to subacute phases in rat models of spinal cord contusion injury

“…In addition, CTSB expressed by the microglia has been demonstrated as a primary driver of neuroinflammation 37 . CTSZ is also indicated as a pathogenic factor and a potential therapeutic target for the management of neuroinflammation 17,38 . However, cathepsins expressed by axonal growth cones play an important role in neuronal plasticity.…”

New Insights into the Role of Cysteine Cathepsins in Neuroinflammation

“…Increasing evidence indicates that microglial activation is an early and ongoing event in several neurodegenerative diseases [ 21 ]. Several studies using in vivo models of neurodegeneration demonstrated marked increases in the expressions of cathepsins B [ 134 ], L [ 135 ], H [ 120 ], C [ 78 ], and X [ 136 ] in different brain regions following LPS-induced neuroinflammation. Among them, microglial cathepsin B has been extensively studied.…”

“…In addition to the striatum, cathepsin X overexpression was detected in other brain areas such as the cerebral cortex, corpus callosum, subventricular zone, and external globus pallidus, and prominent upregulation was mainly restricted to activated microglia and reactive astrocytes ( Figure 4 ). Moreover, the administration of a cathepsin X inhibitor along with LPS injection revealed its potential protective role in neuroinflammation-induced striatal lesions [ 136 ]. Additionally, dendritic cells in aging mouse brains had increased cathepsin X protein levels, which correlated with known markers of neuroinflammation [ 89 ].…”

Evaluation of novel cathepsin-X inhibitors in vitro and in vivo and their ability to improve cathepsin-B-directed antitumor therapy

“…In immune cells, it regulates cell migration, proliferation, maturation, adhesion, phagocytosis, and signal transduction through interaction with integrin receptors [ 6 , 9 ]. In brain tissue, CatX eliminates the neurotrophic activity of γ-enolase by cleaving two amino acid residues at its C-terminus [ 10 ], and is proposed to have an effect on neuron survival and neurite outgrowth [ 11 , 12 ]. Several other molecular targets have been identified as substrates of CatX, including chemokine CXCL-12, bradykinin, kallidin, huntingtin, and profilin-1 [ 6 ].…”