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Cysteine Peptidase Cathepsin X as a Therapeutic Target for Simultaneous TLR3/4-mediated Microglia Activation
dc.creator | Pislar, Anja | |
dc.creator | Nedeljković, Biljana Bozic | |
dc.creator | Perić, Mina | |
dc.creator | Jakos, Tanja | |
dc.creator | Zidar, Nace | |
dc.creator | Kos, Janko | |
dc.date.accessioned | 2022-11-15T15:28:26Z | |
dc.date.available | 2022-11-15T15:28:26Z | |
dc.date.issued | 2022 | |
dc.identifier.issn | 0893-7648 | |
dc.identifier.uri | https://imagine.imgge.bg.ac.rs/handle/123456789/1535 | |
dc.description.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. | en |
dc.publisher | Springer, New York | |
dc.relation | Research Agency of the Republic of Slovenia [P4-0127, J4-4123, J3-9267] | |
dc.relation | Ministry of Education and Science of the Republic of Slovenia [451-03-68/2020-14/200178] | |
dc.relation | Republic of Slovenia | |
dc.relation | Republic of Serbia | |
dc.rights | openAccess | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.source | Molecular Neurobiology | |
dc.subject | Toll-like receptors | en |
dc.subject | Proinflammatory mediators | en |
dc.subject | Neuroprotection | en |
dc.subject | Neuroinflammation | en |
dc.subject | Microglia | en |
dc.subject | Cathepsin X | en |
dc.title | Cysteine Peptidase Cathepsin X as a Therapeutic Target for Simultaneous TLR3/4-mediated Microglia Activation | en |
dc.type | article | |
dc.rights.license | BY | |
dc.citation.epage | 2276 | |
dc.citation.issue | 4 | |
dc.citation.other | 59(4): 2258-2276 | |
dc.citation.rank | M21 | |
dc.citation.spage | 2258 | |
dc.citation.volume | 59 | |
dc.identifier.doi | 10.1007/s12035-021-02694-2 | |
dc.identifier.fulltext | https://imagine.imgge.bg.ac.rs/bitstream/id/125/1532.pdf | |
dc.identifier.pmid | 35066760 | |
dc.identifier.scopus | 2-s2.0-85123495969 | |
dc.identifier.wos | 000745595600002 | |
dc.type.version | publishedVersion |