Neutrophil Extracellular Traps in the Second Decade

Abstract

Nearly 15 years after the first description of neutrophil extracellular traps (NETs), our knowledge concerning this structure has expanded considerably. Initially, NETs were considered solely an elaborate function of the innate immune system to combat invading microorganisms. Successively it became clear that NETs have farther-reaching capabilities. They are involved in a series of pathophysiological mechanisms ranging from inflammation to thrombosis where they fulfill essential functions when produced at the right site and the right time but can have a serious impact when generation or clearance of NETs is inadequately controlled. This review provides a concise overview on the far-reaching functions of NETs in health and disease.

Platelet TLR4 at the crossroads of thrombosis and the innate immune response

“…Neutrophils are the first line of defense against pathogens. Besides phagocytosis and degranulation, a third strategy to combat microbes is the formation of NETs . Very soon after the discovery of NETs and using a mouse model of sepsis, it was shown that platelets are required to fuel the formation of NETs.…”

“…If these reactions occur systemically and are sustained for a long period, as observed in sepsis, they can lead to DIC followed by multiorgan failure and even death. In addition, under sustained sterile inflammatory conditions, they can be involved in the pathogenesis of both arterial or venous thrombotic diseases as well as autoimmune‐related disorders such as lupus, arthritis, or vasculitis …”

“…Besides phagocytosis and degranulation, a third strategy to combat microbes is the formation of NETs. 41 Very soon after the discovery of NETs and using a mouse model of sepsis, it was shown that platelets are required to fuel the formation of NETs. During severe sepsis, platelet TLR4 senses the high levels of circulating LPS and induces platelet binding to adherent neutrophils in the capillaries of the lungs and liver, which not only induces thrombocytopenia but also leads to robust neutrophil activation and the formation of NETs, thereby increasing the capacity of the immune system to trap and kill circulating bacteria.…”

“…In addition, under sustained sterile inflammatory conditions, they can be involved in the pathogenesis of both arterial or venous thrombotic diseases as well as autoimmune-related disorders such as lupus, arthritis, or vasculitis. 41,45…”

Expanding Neutrophil Horizons: New Concepts in Inflammation

“…New insights have been gained into the mechanisms of neutrophil apoptosis and the potential anti- inflammatory consequences of promoting accelerated apoptosis. Furthermore, non-apoptotic forms of neutrophil cell death have been identified that may lead to pro-inflammatory consequences in both infective and autoimmune diseases [32]. …”