Anja Pišlar (Avtor), Biljana Božić Nedeljković (Avtor), Mina Perić (Avtor), Tanja Jakoš (Avtor), Nace Zidar (Avtor), Janko Kos (Avtor)

Povzetek

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.

Ključne besede

mikroglija;tollu-u podobni receptorji;katepsin X;protivnetni mediatorji;nevrovnetje;nevroprotekcija;motnje živčnega sistema;microglia;toll-like receptors;cathepsin X;proinfammatory mediators;neuroinfammation;neuroprotection;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 616-097:616.8
COBISS: 95406083 Povezava se bo odprla v novem oknu
ISSN: 0893-7648
Št. ogledov: 18
Št. prenosov: 7
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: Imunski odziv;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 2258–2276
Letnik: ǂVol. ǂ56
Zvezek: ǂiss. ǂ4
Čas izdaje: 2022
DOI: 10.1007/s12035-021-02694-2
ID: 18594400