Platelet‐neutrophil interaction aggravates vascular inflammation and promotes the progression of atherosclerosis by activating the TLR4/NF‐κB pathway

Abstract

Platelet‐neutrophil interaction is well known for its role in inflammatory diseases; however, its biological role in atherosclerosis (AS) progression remains unclear. Human peripheral blood neutrophils were obtained to compare toll‐like receptor 4 (TLR4), tumor necrosis factor α (TNF‐α), interleukin (IL)‐1β and myeloid‐related proteins 8/14 (Mrp8/14) levels in 22 AS patients with those in 18 healthy controls using quantitative real‐time polymerase chain reaction (qRT‐PCR) and enzyme‐linked immunosorbent assay (ELISA). Meanwhile, mouse marrow neutrophils subjected to different treatment were collected for the ELISA assay, cell apoptosis, and Western blot analysis. Normal diet or high‐fat diet ApoE−/− mice with or without administration of Mrp8/14 antagonist paquinimod were used for plasma collection to measure total cholesterol, triglycerides, low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol, TNF‐α, IL‐1β, Mrp8/14, TLR4, and nuclear factor (NF)‐κB p65 levels. The results showed that Mrp8/14 and TLR4‐mediated inflammatory pathway was activated in neutrophils of AS patients. In vitro experiments demonstrated that platelet‐neutrophil interaction promoted the Mrp8/14 release and inhibited neutrophil apoptosis via P‐selectin. Furthermore, platelet‐neutrophil interaction upregulated TLR4/myeloid differentiation factor 88/NF‐κB pathway. Conversely, Mrp8/14/TLR4/NF‐κB interference alleviated AS progression. In conclusion, Mrp8/14/TLR4/NF‐κB activated by platelet‐neutrophil interaction is an important inflammatory signaling pathway for AS pathogenesis.

Sickle cell vaso-occlusion: The dialectic between red cells and white cells

“…The critical role of SRBC, which are more affected by imbalanced redox physiology, accelerated erythropoiesis, and rheological modifications than by inflammatory pathways is essential to vaso-occlusive processes. At the end of the day, similar inflammatory processes and cellular activation are observed in other pathologies that display vascular inflammation, 232 but the overwhelming pathological microvascular obstruction seen in SCD also requires participation of the altered SRBC and sickling. We recognize that, in what is commonly referred to as the vicious cycle of SCD pathophysiology, inflammatory triggers generated by SRBC destruction and ischemiareperfusion injury appear to be largely responsible for fueling the cellular alterations that result in the adhesion of both less dense SRBC and activated leukocytes to the adhesion molecule-presenting endothelium and heterocellular aggregate formation in microvessels.…”

Cross-Talk of Atherosclerosis and Ischemic Stroke: Dramatic Role of Neutrophils

“…On the platelet surface, there are molecules called P-selectin, which are one of the essential components inducing the platelet's pro-inflammatory effect. P-selectin binds to P-selectin glycoprotein-1 (PSGL-1) on the surface of agranulocytes (monocytes and lymphocytes) and neutrophils and initiates the pro-inflammatory role of platelets in pathways leading to atherosclerosis (1,26,53,56,62,(69)(70)(71)(72)(73).…”

“…Another stimulator of the secretion of inflammatory cytokines is the interaction between P-selectin and PSGL-1 in neutrophils. An additional known function of platelets is the release of chemokines called CCL5 that bind to CCR5 on monocytes and amplified platelets entering into the subendothelial tissue (6,27,42,44,53,62,(69)(70)(71)(72)(73). Referring to the above, there is a cross-talk between platelet and neutrophils that is critical in the atherosclerosis inflammatory process.…”

Serum levels of interleukins and S100A8/A9 correlate with clinical severity in patients with dermatomyositis-associated interstitial lung disease

“…The S100A8/A9 heterodimer is also referred to as calprotectin or MRP8/14. It is abundantly expressed in neutrophils and monocytes and induces proinflammatory cytokines and chemokines through TLR2/TLR4-mediated signaling pathways [ 18 ]. Therefore, S100A8/A9 has been explored as a possible biomarker of disease severity in several autoimmune diseases, including juvenile dermatomyositis [ 19 ], systemic sclerosis [ 20 ] and rheumatoid arthritis [ 21 ].…”