Neutrophil Extracellular Traps and NLRP3 Inflammasome: A Disturbing Duo in Atherosclerosis, Inflammation and Atherothrombosis

Abstract

Atherosclerosis is the formation of plaque within arteries due to overt assemblage of fats, cholesterol and fibrous material causing a blockage of the free flow of blood leading to ischemia. It is harshly impinging on health statistics worldwide because of being principal cause of high morbidity and mortality for several diseases including rheumatological, heart and brain disorders. Atherosclerosis is perpetuated by pro-inflammatory and exacerbated by pro-coagulatory mediators. Besides several other pathways, the formation of neutrophil extracellular traps (NETs) and the activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contribute significantly to the initiation and propagation of atherosclerotic plaque for its worst outcomes. The present review highlights the contribution of these two disturbing processes in atherosclerosis, inflammation and atherothrombosis in their individual as well as collaborative manner.

Netosis in Surgery

“…In addition to inhibiting inflammation caused by MSU crystals in acute gout, colchicine has been shown to be effective (and United States Food and Drug Administration approved (US FDA)) in reducing the risk of acute coronary syndrome, myocardial infarction, stent thrombosis, ischemic stroke, urgent coronary revascularization, and cardiovascular death in high-risk patients. 15,32 (Fig. 6A, B) DNase1 has been shown to improve the procoagulant state in colorectal cancer and resolve NETosis-related thrombosis in both in vitro and in vivo models.…”

“…15 The NLRP3 inflammasome is triggered by cholesterol crystals in atherosclerosis and MSU crystals in gout, as well as other endogenous crystals (calcium oxalate, calcium pyrophosphate dihydrate, and cystine) and exogenous crystals (asbestos, silica, aluminum adjuvant, and titanium dioxide). 2,13,15…”

“…15 Undegraded cholesterol crystals released upon phagolysosomal membrane rupture may also act as DAMPs sensed by pattern recognition receptors, resulting in activation of the innate immune system. 15 Cholesterol crystals thus induce inflammation via "frustrated phagocytosis" and NLRP3 inflammasome activation, with IL-1β and IL-18 release. 15 In turn, this inflammation attracts neutrophils to the site of cholesterol crystals, resulting in potent stimulation of neutrophils by interleukin-1 receptor-associated kinase and Receptor Interacting Protein Kinases (RIPK1-RIPK3)-mixed lineage kinase domain-like protein signaling and NET formation.…”

“…5,9,22,29 NETs also generate ROS and endothelial dysfunction, LDL oxidation and atherosclerotic plaque instability. 15 Examples of NET-related arterial thrombosis include acute coronary syndrome and acute myocardial infarction, acute ischemic stroke, abdominal aortic aneurysm, peripheral vascular disease, and thrombotic microangiopathies (disseminated intravascular coagulation, thrombotic thrombocytopenic purpura). 29 NETs provide a scaffold upon which platelets, fibrin, and erythrocytes can aggregate.…”

The protective role of resveratrol in diabetic wound healing

“…Otherwise, the enhanced ischemia of diabetic wounds can induce inflammatory cascades by impairing cell membranes, causing enhanced expression of endothelial adhesion molecules. In addition, the aggregations of macrophages, neutrophils, and other types of immune cells also can aggravate the inflammation (Singh et al, 2023). Because of a local hyperglycemia and excessive inflammation of diabetic wounds, bacterial and fungus infections are prone to occur, thus attracting various inflammatory cells and immune cells, which can enhance local inflammation and worsen diabetic wounds.…”