CRP Induces NETosis in Heart Failure Patients with or without Diabetes

Abstract

C-reactive protein (CRP) is recognized as a biomarker of chronic, low-grade inflammation associated with vascular disorders. Lately, the role of neutrophils and neutrophil extracellular traps (NETs) has been investigated as a potential source of chronic inflammation and cardiovascular complications. This study investigated NETs as a marker of inflammation in patients with symptomatic heart failure (HF) with or without type 2 diabetes (T2DM) and examined the correlation between NETs and CRP. We performed a noninterventional study including patients with HF with or without T2DM, T2DM, and a healthy control (HC) group. NETs and other inflammatory markers in serum were measured by ELISA. The release of NETs (NETosis) in vitro under various stimuli was measured by confocal microscopy. The levels of NETs in the serum of HF patients were significantly higher compared with HC (112%). Serum CRP concentrations were significantly increased in HF and HF plus T2DM patients compared with HC, and a positive correlation was observed between serum CRP and NETs levels. Neutrophils from HF and HF plus T2DM patients underwent in vitro NETs release faster than T2DM and HC without any stimuli. In vitro, serum collected from the HF and the HF plus T2DM group induced NETosis in healthy neutrophils significantly more when compared with HC and T2DM, which was prevented by depletion from CRP. We confirmed in vitro that CRP induces a concentration-dependent NETs synthesis. This study proposes a mechanism by which CRP increases the risk of future cardiovascular events and supports mounting evidences on the role of neutrophils in chronic low-grade inflammation associated with HF.

Angiopoietin 1 release from Human Neutrophils is Independent from Neutrophil Extracellular Traps (NETs)

“…More recently, we and other groups reported elevated levels of circulating NETs in T2DM patients and an increase in their neutrophil capacity in vitro to release NETs (15,43,44). Furthermore, we observed an increase in circulating NETs and corresponding release in HF patients, the latter reaching a maximum in HF + T2DM (15). The results from this study con rm that NETs release is signi cantly increased in clinical HF and more so in patients with HF and T2DM.…”

“…Heart failure (HF) is a pro-in ammatory condition, in which the magnitude of in ammation is associated with the disease severity, being maximal in acute decompensated heart failure (ADHF) patients. Lately, we and other groups reported an increase of NETs formation, either circulating or under in vitro neutrophil stimulation in type 2 diabetic (T2DM) patients (13)(14)(15) and in patients suffering from HF with or without T2DM (15). HF classi cation is based on left ventricular ejection fraction (LVEF), which can be reduced (HFrEF, LVEF ≤ 40%) or preserved (HFpEF, LVEF ≥ 50%), each with distinct phenotypes (16).…”

Plasma neutrophil extracellular trap level is modified by disease severity and inhaled corticosteroids in chronic inflammatory lung diseases

“…In addition, it was also demonstrated that plasma CRP were inversely associated with FEV1 22 . Furthermore, it was shown that CRP induces a concentration-dependent NET synthesis 23 . A possible hypothesis can be that impaired lung function leads to a systemic inflammation with elevated CRP level which induces NETosis.…”

A network-informed analysis of SARS-CoV-2 and hemophagocytic lymphohistiocytosis genes’ interactions points to Neutrophil extracellular traps as mediators of thrombosis in COVID-19

“…NET release can be triggered by various inflammatory mediators found elevated in severe COVID-19, including CRP, IL-1β, IL-6 and IL-8 [50]. There is also a positive correlation between circulating serum of IL-6, IL-8, CRP and NET levels [60]. NETs are found in a variety of conditions such as infection, malignancy, atherosclerosis, and autoimmune diseases with reports now emerging that describe their presence in COVID-19 [9,[61][62][63].…”