Class I phosphoinositide 3-kinases control sustained NADPH oxidase activation in adherent neutrophils.
Biochem Pharmacol
; 178: 114088, 2020 08.
Article
en En
| MEDLINE
| ID: mdl-32531347
ABSTRACT
Phagocytes, especially neutrophils, can produce reactive oxygen species (ROS), through the activation of the NADPH oxidase (NOX2). Although this enzyme is crucial for host-pathogen defense, ROS production by neutrophils can be harmful in several pathologies such as cardiovascular diseases or chronic pulmonary diseases. The ROS production by NOX2 involves the assembly of the cytosolic subunits (p67phox, p47phox, and p40phox) and Rac with the membrane subunits (gp91phox and p22phox). Many studies are devoted to the activation of NOX2. However, the mechanisms that cause NADPH oxidase deactivation and thus terminate ROS production are not well known. Here we investigated the ability of class I phosphoinositide 3-kinases (PI3Ks) to sustain NADPH oxidase activation. The NADPH oxidase activation was triggered by seeding neutrophil-like PLB-985 cells, or human neutrophils on immobilized fibrinogen. Adhesion of the neutrophils, mediated by ß2 integrins, induced activation of the NADPH oxidase and translocation of the cytosolic subunits at the plasma membrane. Inhibition of class I PI3Ks, and especially PI3Kß, terminated ROS production. This deactivation of NOX2 is due to the release of the cytosolic subunits, p67phox and p47phox from the plasma membrane. Overexpression of an active form of Rac 1 did not prevent the drop of ROS production upon inhibition of class I PI3Ks. Moreover, the phosphorylation of p47phox at S328, a potential target of kinases activated by the PI3K pathway, was unchanged. Our results indicate that the experimental downregulation of class I PI3K products triggers the plasma membrane NADPH oxidase deactivation. Release of p47phox from the plasma membrane may involve its PX domains that bind PI3K products.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Especies Reactivas de Oxígeno
/
NADPH Oxidasas
/
Fosfatidilinositol 3-Quinasas
/
Neutrófilos
Límite:
Humans
Idioma:
En
Revista:
Biochem Pharmacol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Francia