期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 51, 期 9, 页码 2274-2280出版社
WILEY
DOI: 10.1002/eji.202049029
关键词
CXCR1; CXCR2; Chemotaxis; Interleukin 8; Neutrophils; Neutrophil extracellular traps; ROS; Reactive oxygen species
类别
资金
- MINECO [SAF2017-83267-C2-1-R]
- European Union's Horizon 2020 research and innovation program [635122-PROCROP]
- Fundacion de la Asociacion Espanola Contra el Cancer (AECC)
- la Caixa Banking Foundation [LCF/BQ/LR18/11640014]
- AECC
IL-8 plays a key role in guiding neutrophils and monocytes/macrophages through chemotaxis; IL-8-induced NETosis is less dependent on G-proteins and can be inhibited by extracellular Ca+2 chelation; NETosis can be more readily inhibited with anti-CXCR1 antibody than chemotaxis.
In humans, IL-8 (CXCL8) is a key chemokine for chemotaxis of polymorphonuclear leukocytes and monocytes/macrophages when acting on CXCR1 and CXCR2. CXCL8 activity on neutrophils includes chemotaxis and eliciting the extrusion of neutrophil extracellular traps (NETs). In this study, we show that concentrations of IL-8 that induce NETosis surpass in at least one order of magnitude those required to elicit chemoattraction in human neutrophils. IL-8-induced NETosis was less dependent on G-proteins than migration, while extracellular Ca+2 chelation similarly inhibited both processes. Reactive oxygen species (ROS) were more important for NETosis than for chemotaxis as evidenced by neutralization with N-acetyl -cysteine. Interestingly, selective blockade with anti-CXCR1 mAb inhibited NETosis much more readily than chemotaxis, while pharmacological inhibition of both CXCR1 and CXCR2, or selective inhibition for CXCR2 alone, similarly inhibited both functions. Together, these results propose a model according to which low concentrations of IL-8 in a gradient attract neutrophils to the inflammatory foci, while high receptor-saturating concentrations of IL-8 give rise to NETosis once leukocytes reach the core of the inflammatory insult.
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