Cysteine Peptidase Cathepsin X as a Therapeutic Target for Simultaneous TLR3/4-mediated Microglia Activation.

Abstract

Microglia are resident macrophages in the central nervous system that are involved in immune responses driven by Toll-like receptors (TLRs). Microglia-mediated inflammation can lead to central nervous system disorders, and more than one TLR might be involved in these pathological processes. The cysteine peptidase cathepsin X has been recognized as a pathogenic factor for inflammation-induced neurodegeneration. Here, we hypothesized that simultaneous TLR3 and TLR4 activation induces synergized microglia responses and that these phenotype changes affect cathepsin X expression and activity. Murine microglia BV2 cells and primary murine microglia were exposed to the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) and the TLR4 ligand lipopolysaccharide (LPS), individually and simultaneously. TLR3 and TLR4 co-activation resulted in increased inflammatory responses compared to individual TLR activation, where poly(I:C) and LPS induced distinct patterns of proinflammatory factors together with different patterns of cathepsin X expression and activity. TLR co-activation decreased intracellular cathepsin X activity and increased cathepsin X localization at the plasma membrane with concomitant increased extracellular cathepsin X protein levels and activity. Inhibition of cathepsin X in BV2 cells by AMS36, cathepsin X inhibitor, significantly reduced the poly(I:C)- and LPS-induced production of proinflammatory cytokines as well as apoptosis. Additionally, inhibiting the TLR3 and TLR4 common signaling pathway, PI3K, with LY294002 reduced the inflammatory responses of the poly(I:C)- and LPS-activated microglia and recovered cathepsin X activity. We here provide evidence that microglial cathepsin X strengthens microglia activation and leads to subsequent inflammation-induced neurodegeneration. As such, cathepsin X represents a therapeutic target for treating neurodegenerative diseases related to excess inflammation.

• Authors: Anja Pišlar, Biljana Božić Nedeljković, Mina Perić, Tanja Jakoš, Nace Zidar, Janko Kos
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 59 Issue 4 Pg. 2258-2276 (Apr 2022) ISSN: 1559-1182 [Electronic] United States
• PMID: 35066760 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• Ligands
• Lipopolysaccharides
• TLR3 protein, mouse
• Toll-Like Receptor 3
• Toll-Like Receptor 4
• Cysteine
• Poly I-C

Topics

• Animals
• Cysteine (metabolism)
• Inflammation (metabolism)
• Ligands
• Lipopolysaccharides (pharmacology)
• Mice
• Microglia (metabolism)
• Poly I-C (adverse effects, metabolism)
• Toll-Like Receptor 3 (metabolism)
• Toll-Like Receptor 4 (metabolism)