4.6 Article

Glutaredoxin 1 up-regulates deglutathionylation of α4 integrin and thereby restricts neutrophil mobilization from bone marrow

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 8, Pages 2616-2627

Publisher

ELSEVIER
DOI: 10.1074/jbc.RA118.006096

Keywords

glutathionylation; reactive oxygen species (ROS); integrin; neutrophil; inflammation; alpha 4 integrin; glutaredoxin; immune response; neutrophil mobilization; vascular cell adhesion molecular 1 (VCAM-1)

Funding

  1. National Science Foundation of China [81803648, 81770580, 31701098, 81803183, 81470931, 31401188]
  2. Sichuan University [2018SCUH0039, 2014ASCU11042]
  3. Applied Basic Research Program of Sichuan Province [2016JY0027]
  4. Science Foundation for Excellent Youth Scholars of Sichuan University [2016SCU04A08]
  5. Sichuan Association for Science and Technology [2018RCTJ04]

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alpha 4 integrin plays a crucial role in retention and release of neutrophils from bone marrow. Although alpha 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 alpha 4 integrin in neutrophils increases the binding of neutrophil-associated alpha 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 alpha 4 glutathionylation and subsequently enhanced neutrophil egress from the bone marrow. Corroborating this observation, intravenous injection of recombinant Grx1 into mice inhibited alpha 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 alpha 4 integrin affinity and neutrophil mobilization from the bone marrow under physiological conditions.

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