Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, Chemokines, CXCL8, Nitration, Neutrophils, Inflammation, Chemotaxis, SOLUTION NMR CHARACTERIZATION, GLYCOSAMINOGLYCAN INTERACTIONS, DIMER BINDING, PEROXYNITRITE, MONOMER, INTERLEUKIN-8, CXCR1, Humans, Interleukin-8, Leukocytes, Peroxynitrous Acid, 11A4220N|11A4222N#55341643, C16/17/010#54271312, 0601 Biochemistry and Cell Biology, 0606 Physiology, 1103 Clinical Sciences, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics, 3211 Oncology and carcinogenesis

Abstract:

Chemokine 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.