Neutrophil GM-CSF receptor dynamics in acute lung injury.

ABSTRACT: GM-CSF is important in regulating acute, persistent neutrophilic inflammation in certain settings, including lung injury. Ligand binding induces rapid internalization of the GM-CSF receptor (GM-CSFR?) complex, a process essential for signaling. Whereas GM-CSF controls many aspects of neutrophil biology, regulation of GM-CSFR? expression is poorly understood, particularly the role of GM-CSFR? in ligand clearance and whether signaling is sustained despite major down-regulation of GM-CSFR? surface expression. We established a quantitative assay of GM-CSFR? surface expression and used this, together with selective anti-GM-CSFR antibodies, to define GM-CSFR? kinetics in human neutrophils, and in murine blood and alveolar neutrophils in a lung injury model. Despite rapid sustained ligand-induced GM-CSFR? loss from the neutrophil surface, which persisted even following ligand removal, pro-survival effects of GM-CSF required ongoing ligand-receptor interaction. Neutrophils recruited to the lungs following LPS challenge showed initially high mGM-CSFR? expression, which along with mGM-CSFR? declined over 24 hr; this was associated with a transient increase in bronchoalveolar lavage fluid (BALF) mGM-CSF concentration. Treating mice in an LPS challenge model with CAM-3003, an anti-mGM-CSFR? mAb, inhibited inflammatory cell influx into the lung and maintained the level of BALF mGM-CSF. Consistent with neutrophil consumption of GM-CSF, human neutrophils depleted exogenous GM-CSF, independent of protease activity. These data show that loss of membrane GM-CSFR? following GM-CSF exposure does not preclude sustained GM-CSF/GM-CSFR? signaling and that this receptor plays a key role in ligand clearance. Hence neutrophilic activation via GM-CSFR may play an important role in neutrophilic lung inflammation even in the absence of high GM-CSF levels or GM-CSFR? expression.

SUBMITTER: De Alessandris S 

PROVIDER: S-EPMC6850700 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature