Neutrophil extracellular traps induced by IL-8 aggravate atherosclerosis via activation NF-κB signaling in macrophages.

Abstract

Here, we sought to explore the underlying role of interleukin (IL)-8 in neutrophil extracellular traps (NETs) formation during atherosclerosis (AS). The concentration of pro-inflammatory cytokines IL-8, IL-6 and IL-1β was determined by enzyme-linked immunosorbent assay (ELISA). NETs formation was evaluated by immunofluorescence and myeloperoxidase (MPO)-DNA complex ELISA. The mRNA levels of IL-8 and Toll-like receptor 9 (TLR9) were measured by quantitative real-time PCR (qRT-PCR). The phosphorylation levels of NF-κB p65 were detected by western blotting. The hematoxylin and eosin (H&E) staining of atherosclerotic lesion areas was performed in ApoE-deficiency mice. Results showed that patients with AS showed higher serum levels of IL-8, a pro-inflammatory cytokine and NETs. IL-8 interacted with its receptor CXC chemokine receptor 2 (CXCR2) on neutrophils, leading to the formation of NETs via Src and extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPK) signaling to aggravate AS progression in vivo. PMA-induced NETosis directly upregulated the TLR9/NF-κB pathway in macrophages and subsequently initiated the release of IL-8. Our data reveal a neutrophil-macrophage interaction in AS progression, and indicate that NETs represent as a novel therapeutic target in treatment of AS and other cardiovascular diseases (CVD).

• Authors: Zhujun An, Jiawen Li, Jiangbo Yu, Xiaoli Wang, Hailai Gao, Wei Zhang, Zeren Wei, Jianchun Zhang, Yinli Zhang, Jiyi Zhao, Xiao Liang
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 18 Issue 21 Pg. 2928-2938 (Nov 2019) ISSN: 1551-4005 [Electronic] United States
• PMID: 31496351 (Publication Type: Journal Article)

Chemical References

• CXCL8 protein, human
• CXCR2 protein, human
• IL1B protein, human
• IL6 protein, human
• Interleukin-1beta
• Interleukin-6
• Interleukin-8
• RELA protein, human
• Receptors, Interleukin-8B
• TLR9 protein, human
• Toll-Like Receptor 9
• Transcription Factor RelA
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Atherosclerosis (pathology)
• Cell Line, Tumor
• Enzyme-Linked Immunosorbent Assay
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Extracellular Traps (immunology)
• Gene Expression Regulation
• Humans
• Interleukin-1beta (blood)
• Interleukin-6 (blood)
• Interleukin-8 (blood, metabolism)
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophils (immunology)
• Receptors, Interleukin-8B (metabolism)
• Signal Transduction
• Toll-Like Receptor 9 (metabolism)
• Transcription Factor RelA (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)