The Neutrophil Secretome as a Crucial Link between Inflammation and Thrombosis

Abstract

Cardiovascular diseases are a leading cause of death. Blood–cell interactions and endothelial dysfunction are fundamental in thrombus formation, and so further knowledge of the pathways involved in such cellular crosstalk could lead to new therapeutical approaches. Neutrophils are secretory cells that release well-known soluble inflammatory signaling mediators and other complex cellular structures whose role is not fully understood. Studies have reported that neutrophil extracellular vesicles (EVs) and neutrophil extracellular traps (NETs) contribute to thrombosis. The objective of this review is to study the role of EVs and NETs as key factors in the transition from inflammation to thrombosis. The neutrophil secretome can promote thrombosis due to the presence of different factors in the EVs bilayer that can trigger blood clotting, and to the release of soluble mediators that induce platelet activation or aggregation. On the other hand, one of the main pathways by which NETs induce thrombosis is through the creation of a scaffold to which platelets and other blood cells adhere. In this context, platelet activation has been associated with the induction of NETs release. Hence, the structure and composition of EVs and NETs, as well as the feedback mechanism between the two processes that causes pathological thrombus formation, require exhaustive analysis to clarify their role in thrombosis.

Neutrophil Extracellular Trap-Driven Occlusive Diseases

“…Thromboembolism occurs if a partial thrombus detaches from the vessel walls, floats in the circulation, and finally, fully occludes a distal part of the vessel. Due to its narrow relationship with inflammation, thrombosis plays a critical role in the pathophysiology of various diseases [ 10 , 11 ]. A number of factors can initiate thrombosis, but the role of NETs in thrombogenesis was reportedly unique [ 12 ].…”

“…Cardiovascular diseases are the most common diseases with the highest death rates worldwide [ 11 ]. In myocardial infarction, atherosclerotic plaque rupture with subsequent thrombogenesis is considered the essential event in arterial occlusions, because it jeopardizes the epicardial flow.…”

“…In myocardial infarction, atherosclerotic plaque rupture with subsequent thrombogenesis is considered the essential event in arterial occlusions, because it jeopardizes the epicardial flow. However, the fundamental mechanisms that cause coronary occlusions are still partially elusive [ 11 , 16 ]. Neutrophils have been shown to exacerbate vascular occlusion, and their blood concentration is considered one of the most reliable indicators for acute coronary events.…”

“…Consequently, the mechanism of NETs formation has to be explored for every single condition, and then, therapeutic strategies have to be developed in a condition-specific manner. NE, MPO, PAD4, and extracellular DNA are promising targets for suppressing excessive NETs formation [ 11 , 28 ] and are, therefore, currently the focus of drug development ( Figure 3 ). Among these, the inhibition of PAD4 and the treatment with DNase1 are the most promising candidates for NETs-driven occlusions [ 91 ].…”

Platelet-Therapeutics to Improve Tissue Regeneration and Wound Healing—Physiological Background and Methods of Preparation

“…Leukocytes, in turn, release cytokines and chemokines to modulate inflammation. Moreover, neutrophils can release reactive oxygen species as well as their nuclear content to form neutrophil extracellular traps (NETs) to fight pathogens [ 43 ].…”