Inhibition of NETosis for treatment purposes: friend or foe?

Abstract

Active neutrophils participate in innate and adaptive immune responses through various mechanisms, one of the most important of which is the formation and release of neutrophil extracellular traps (NETs). The NETs are composed of network-like structures made of histone proteins, DNA and other released antibacterial proteins by activated neutrophils, and evidence suggests that in addition to the innate defense against infections, NETosis plays an important role in the pathogenesis of several other non-infectious pathological states, such as autoimmune diseases and even cancer. Therefore, targeting NET has become one of the important therapeutic approaches and has been considered by researchers. NET inhibitors or other molecules involved in the NET formation, such as the protein arginine deiminase 4 (PAD4) enzyme, an arginine-to-citrulline converter, participate in chromatin condensation and NET formation, is the basis of this therapeutic approach. The important point is whether complete inhibition of NETosis can be helpful because by inhibiting this mechanism, the activity of neutrophils is suppressed. In this review, the biology of NETosis and its role in the pathogenesis of some important diseases have been summarized, and the consequences of treatment based on inhibition of NET formation have been discussed.

Coagulation and complement: Key innate defense participants in a seamless web

“…The value in deciphering the intricacies of this web of molecular and cellular relationships on disease outcome, is underlined by the overwhelming success of the terminal pathway anti-C5 antibodies, eculizumab and ravulizumab, in preventing the devastating thrombotic manifestations of aHUS and PNH ( 13 , 14 , 193 ). It is also evident by exciting new advances in our understanding of these interactive pathways, as several newer agents that target, for example, MASP2, FB, FD, C3, the C5a-C5aR axis, BK, BR, FXII/FXIIa, FXI/FXIa, polyanions, platelets, neutrophils and NETs, are being evaluated in clinical studies that are at various stages of development, and in many cases with promising results (reviewed in ( 193 , 252 , 253 ). And more are on the horizon.…”

The Expanding Role of Extracellular Traps in Inflammation and Autoimmunity: The New Players in Casting Dark Webs

“…(2) Target enzymes required for digesting either the nuclear envelope, outer cell membrane, or citrullination of histones (PAD family, NE, MPO, GASDERMIN D). Each of these distinct critical components will be considered and discussed briefly as more diverse treatment options have been extensively reviewed recently [ 247 , 248 ].…”

Molecular mechanisms and therapeutic target of NETosis in diseases

“…The release of inflammatory mediators is augmented by NETosis products such as cfDNA (Figure 3). 80 Research has indicated that extracellular cold‐inducible RNA‐binding protein activated receptor on myeloid cells‐1 (TREM‐1) leading to the production of neutrophils with intercellular adhesion molecule‐1, which is involved in Rho GTPase to promote NETosis in sepsis 81 . Extracellular histones produced by NETosis may act as DAMPs, causing inflammation and organ damage 82 .…”