Abstract
α4 integrin plays a crucial role in retention and release of neutrophils from bone marrow. Although α4 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 α4 integrin in neutrophils increases the binding of neutrophil-associated α4 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 α4 glutathionylation and subsequently enhanced neutrophil egress from the bone marrow. Corroborating this observation, intravenous injection of recombinant Grx1 into mice inhibited α4 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 α4 integrin affinity and neutrophil mobilization from the bone marrow under physiological conditions.
Highlights
␣4 integrin plays a crucial role in retention and release of neutrophils from bone marrow
As stress conditions induce elevated level of reactive oxygen species (ROS), we speculated that glutaredoxin 1 (Grx1)- and ROS-mediated ␣4 integrin glutathionylation might be involved in neutrophil mobilization from the bone marrow
No band was detected in neutrophil-like differentiated HL60 cell lysates, there was a band corresponding to the size of ␣4 integrin after formyl-methionyl-leucyl-phenylalanine stim
Summary
␣4 integrin plays a crucial role in retention and release of neutrophils from bone marrow. 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. We demonstrated that ROS induced ␣4 integrin glutathionylation and subsequently regulated the adhesion of neutrophils to endothelial cells. As stress conditions induce elevated level of ROS, we speculated that Grx1- and ROS-mediated ␣4 integrin glutathionylation might be involved in neutrophil mobilization from the bone marrow. This study reveals that Grx1-mediated and ROS-induced ␣4 integrin glutathionylation are important physiological regulatory mechanisms controlling ␣4 integrin functions in neutrophils and participate in bone marrow neutrophil mobilization under stress conditions
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