Abstract
AbstractChemokine CXCL8 is a key facilitator of the human host immune response, mediating neutrophil migration, and activation at the site of infection and injury. The oxidative burst is an important effector mechanism which leads to the generation of reactive nitrogen species (RNS), including peroxynitrite. The current study was performed to determine the potential for nitration to alter the biological properties of CXCL8 and its detection in human disease. Here, we show peroxynitrite nitrates CXCL8 and thereby regulates neutrophil migration and activation. The nitrated chemokine was unable to induce transendothelial neutrophil migration in vitro and failed to promote leukocyte recruitment in vivo. This reduced activity is due to impairment in both G protein-coupled receptor signaling and glycosaminoglycan binding. Using a novel antibody, nitrated CXCL8 was detected in bronchoalveolar lavage samples from patients with pneumonia. These findings were validated by mass spectrometry. Our results provide the first direct evidence of chemokine nitration in human pathophysiology and suggest a natural mechanism that limits acute inflammation.
Funder
NIH
Kidney Research UK
British Heart Foundation
Engineering and Physical Sciences Research Council
FWO-Vlaanderen PhD fellowship
Norther Accelerator Award
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Cellular and Molecular Neuroscience,Pharmacology,Molecular Biology,Molecular Medicine
Cited by
1 articles.
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