Glutaredoxin 1 up-regulates deglutathionylation of ?4 integrin and thereby restricts neutrophil mobilization from bone marrow.

ABSTRACT: ?4 integrin plays a crucial role in retention and release of neutrophils from bone marrow. Although ?4 integrin is known to be a potential target of reactive oxygen species (ROS)-induced cysteine glutathionylation, the physiological significance and underlying regulatory mechanism of this event remain elusive. Here, using in vitro and in vivo biochemical and cell biology approaches, we show that physiological ROS-induced glutathionylation of ?4 integrin in neutrophils increases the binding of neutrophil-associated ?4 integrin to vascular cell adhesion molecule 1 (VCAM-1) on human endothelial cells. This enhanced binding was reversed by extracellular glutaredoxin 1 (Grx1), a thiol disulfide oxidoreductase promoting protein deglutathionylation. Furthermore, in a murine inflammation model, Grx1 disruption dramatically elevated ?4 glutathionylation and subsequently enhanced neutrophil egress from the bone marrow. Corroborating this observation, intravenous injection of recombinant Grx1 into mice inhibited ?4 glutathionylation and thereby suppressed inflammation-induced neutrophil mobilization from the bone marrow. Taken together, our results establish ROS-elicited glutathionylation and its modulation by Grx1 as pivotal regulatory mechanisms controlling ?4 integrin affinity and neutrophil mobilization from the bone marrow under physiological conditions.

SUBMITTER: You Y 

PROVIDER: S-EPMC6393595 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature