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Cysteine peptidase cathepsin X as a therapeutic target for simultaneous TLR3/4-mediated microglia activationPišlar, Anja ...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.Source: Molecular neurobiology. - ISSN 0893-7648 (Vol. 56, iss. 4, 2022, str. 2258–2276)Type of material - article, component part ; adult, seriousPublish date - 2022Language - englishCOBISS.SI-ID - 95406083
Author
Pišlar, Anja |
Božić, Biljana |
Perić, Mina, biokemik |
Jakoš, Tanja |
Zidar, Nace |
Kos, Janko, 1959-
Topics
Imunski odziv |
mikroglija |
tollu-u podobni receptorji |
katepsin X |
protivnetni mediatorji |
nevrovnetje |
nevroprotekcija |
motnje živčnega sistema |
microglia |
toll-like receptors |
cathepsin X |
proinfammatory mediators |
neuroinfammation |
neuroprotection
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Database name | Field | Year |
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Pišlar, Anja | 32035 |
Božić, Biljana | ![]() |
Perić, Mina, biokemik | ![]() |
Jakoš, Tanja | 39198 |
Zidar, Nace | 28905 |
Kos, Janko, 1959- | 04648 |
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