The impact of NETosis on hematological malignancies as a promising therapeutic target

Abstract

NETosis is a regulated cell death pathway primarily used by neutrophils to eliminate abnormal cells and pathogens, including bacteria, protozoa, fungi, and viruses, via neutrophil extracellular traps (NETs) production (1). Extracellular trap (ET) structure consists of DNA, chromatin, histones, granules, cytosolic and antimicrobial proteins produced against pathogens that can be formed by neutrophils (NETs), macrophages (METs), eosinophils (EETs), mast cells (MCETs), and basophils (BETs) involved in the antimicrobial response, thrombosis, diabetes, sepsis, immune regulation, cardiac function, cancer progression, metastasis, and chemoresistance (2). NETs are the first discovered ones released by activated neutrophils, comprising 50-70% of all white blood cells, and considered the first line of defense against pathogens, inflammation, cancer cells, and environmental exposures. Neutrophils regulate innate and adaptive immune systems, where activated neutrophils eliminate abnormal cells and pathogens via three major pathways: NETosis via NET formation, phagocytosis, and the release of cytotoxic enzymes called degranulation (3, 4).NETosis was first described by Takoma et al. in 1996 (2) and characterized in detail by Brinkman et al. in 2004 (3). NETosis is triggered via various signals and pathways including elevated intracellular calcium levels via b2 integrin, increased reactive oxygen species (ROS) levels, membrane surface receptors such as CD18, toll-like receptor 1 (TLR1), phorbol myristate acetate (PMA), nucleotide oligomerization domain (NOD)-like receptor 2, intracellular signaling cascades including SYK-PI3K-mTorc2 AND Raf-MEK-ERK-MAP kinase, cytokines and chemokines (IL-1, IL-18, TNF), changes in the pH, presence of bacterial toxins and proteins such as lipopolysaccharides (LPS) (5). NETosis is categorized into suicidal and vital NETosis depending on whether neutrophil integrity and function are preserved. Vital NETosis is independent of NADPH oxidase (NOX), in which neutrophils remain vital and take approximately 30 minutes. It is triggered by complement proteins, pathogens, and activated platelets via activation of TLR-2, TLR-4, and complement receptor 3 (CR3) that leads to activation of peptidyl arginine deiminase-4 (PAD4) enzyme involved in the chromatin decondensation (6). After activation, PAD4 enters the nucleus, triggering citrullinated H3 (CitH3) to activate chromatin decondensation. CitH3 is a biomarker associated with NETosis, NET production, venous thromboembolism, and