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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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MD5: B6A1F14256F78603B69F6FCE1A202178
URL - Source URL, Visit
https://link.springer.com/article/10.1007/s12035-021-02694-2
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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
UDC:
616-097:616.8
ISSN on article:
0893-7648
DOI:
10.1007/s12035-021-02694-2
COBISS.SI-ID:
95406083
Publication date in RUL:
14.04.2023
Views:
658
Downloads:
76
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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
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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