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Cysteine peptidase cathepsin X as a therapeutic target for simultaneous TLR3/4-mediated microglia activation
ID Pišlar, Anja (Author), ID Božić Nedeljković, Biljana (Author), ID Perić, Mina (Author), ID Jakoš, Tanja (Author), ID Zidar, Nace (Author), ID Kos, Janko (Author)

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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.

Language:English
Keywords:microglia, toll-like receptors, cathepsin X, proinfammatory mediators, neuroinfammation, neuroprotection
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Publication status:Published
Publication version:Version of Record
Year:2022
Number of pages:Str. 2258–2276
Numbering:Vol. 59, iss. 4
PID:20.500.12556/RUL-145265 This link opens in a new window
UDC:616-097:616.8
ISSN on article:0893-7648
DOI:10.1007/s12035-021-02694-2 This link opens in a new window
COBISS.SI-ID:95406083 This link opens in a new window
Publication date in RUL:14.04.2023
Views:304
Downloads:58
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Record is a part of a journal

Title:Molecular neurobiology
Shortened title:Mol. neurobiol.
Publisher:Springer Nature
ISSN:0893-7648
COBISS.SI-ID:25975552 This link opens in a new window

Licences

License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

Language:Slovenian
Keywords:mikroglija, receptorji TLR, katepsin X, protivnetni mediatorji, nevrovnetje, nevroprotekcija, motnje živčnega sistema, imunski odziv

Projects

Funder:ARRS - Slovenian Research Agency
Project number:P4-0127
Name:Farmacevtska biotehnologija: znanost za zdravje

Funder:ARRS - Slovenian Research Agency
Project number:J4-4123
Name:Inhibitorji cisteinskih karboksipeptidaz kot regulatorji avtoimunskih in nevrodegenerativnih procesov

Funder:ARRS - Slovenian Research Agency
Project number:J3-9267
Name:Zaviranje aktivnosti katepsina X kot nov pristop za zdravljenje Parkinsonove bolezni

Funder:Other - Other funder or multiple funders
Funding programme:Republic of Slovenia, Ministry of Education, Science and Sport
Project number:451–03-68/2020–14/200178

Funder:Other - Other funder or multiple funders
Funding programme:Republic of Slovenia, Bilateral Projects

Funder:Other - Other funder or multiple funders
Funding programme:Republic of Serbia, Bilateral Projects

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