Immunity and Inflammation Theme, Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Department of Biochemistry and Molecular Biology, Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch, Galveston, TX, 77555, USA.
Cell Mol Life Sci. 2023 Jan 9;80(1):35. doi: 10.1007/s00018-022-04663-x.
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.
趋化因子 CXCL8 是人体宿主免疫反应的关键促进剂，介导中性粒细胞在感染和损伤部位的迁移和激活。氧化爆发是一种重要的效应机制，导致活性氮物种 (RNS) 的产生，包括过氧亚硝酸盐。本研究旨在确定硝化作用改变 CXCL8 生物学特性及其在人类疾病中检测的潜力。在这里，我们表明过氧亚硝酸盐硝化 CXCL8，从而调节中性粒细胞的迁移和激活。硝化趋化因子在体外不能诱导跨内皮中性粒细胞迁移，也不能促进体内白细胞募集。这种活性降低是由于 G 蛋白偶联受体信号和糖胺聚糖结合受损所致。使用一种新型抗体，在肺炎患者的支气管肺泡灌洗液样本中检测到硝化 CXCL8。这些发现通过质谱法得到了验证。我们的研究结果为人类病理生理学中趋化因子硝化提供了直接证据，并提出了一种限制急性炎症的天然机制。
