Xiaoliang Wang (Avtor), Damjan Avsec (Avtor), Aleš Obreza (Avtor), Shida Yousefi (Avtor), Irena Mlinarič-Raščan (Avtor), Hans-Uwe Simon (Avtor)

Povzetek

Adhesion receptors, such as CD44, have been shown to activate receptor interacting protein kinase-3 (RIPK3)-mixed lineage kinase-like (MLKL) signaling, leading to a non-apoptotic cell death in human granulocyte/macrophage colony-stimulating factor (GM-CSF) - primed neutrophils. The signaling events of this necroptotic pathway, however, remain to be investigated. In the present study, we report the design, synthesis, and characterization of a series of novel serine protease inhibitors. Two of these inhibitors, compounds 1 and 3, were able to block CD44-triggered necroptosis in GM-CSF-primed neutrophils. Both inhibitors prevented the activation of MLKL, p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3%-kinase (PI3K), hence blocking the increased levels of reactive oxygen species (ROS) required for cell death. Although compounds one and three partially inhibited isolated human neutrophil elastase (HNE) activity, we obtained no pharmacological evidence that HNE is involved in the initiation of this death pathway within a cellular context. Interestingly, neither serine protease inhibitor had any effect on FAS receptor-mediated apoptosis. Taken together, these results suggest that a serine protease is involved in non-apoptotic CD44-triggered RIPK3-MLKL-dependent neutrophil cell death, but not FAS receptor-mediated caspase-dependent apoptosis. Thus, a pharmacological block on serine proteases might be beneficial for preventing exacerbation of disease in neutrophilic inflammatory responses.

Ključne besede

necroptosis;neutrophil;serine protease;signal transduction;small molecule inhibitor;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 576.36
COBISS: 48117763 Povezava se bo odprla v novem oknu
ISSN: 1663-9812
Št. ogledov: 93
Št. prenosov: 31
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: nekroptoza;serinske proteaze;zaviralci molekul;receptor CD44;Apoptoza;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 1-10
Zvezek: ǂVol ǂ11
Čas izdaje: 2021
DOI: 10.3389/fphar.2020.614928
ID: 16608041