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).

Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response

“…NETs contain several DAMPs that may be recognized by TLR4/9 [44]. TLR signals mediate the proinflammatory effect of NETs on several host cells [45,46]. Many reports have demonstrated that NETs could upregulate TLR9 expression in colon cancer cells and that TLR is an upstream regulator of COX2 expression [36,47,48].…”

Serum cell-free DNA and progression of diabetic kidney disease: a prospective study

“…A commercially available kit (Q33120, USA, Thermo), which was described in a previous study,5 was used to determine the concentrations of serum cfDNA. All experimental procedures were carried out according to the manufacturer’s instructions.…”

Multiple Roles for Chemokines in Neutrophil Biology

“…Release of NETs is induced by CXCR2 activation via Src, extracellular signal-regulated kinase (ERK), and p38/MAPK signaling (86). The CXCL1-CXCR2 axis has been associated to NET formation and neutrophil degranulation in a model of deep vein thrombosis in mice (87) and in circulating and airway mucosal neutrophils of chronic obstructive pulmonary disease (COPD) patients.…”