Post-Translational Modifications in NETosis and NETs-Mediated Diseases

Abstract

: Neutrophils undergo a unique form of cell death that generates neutrophil extracellular traps (NETs) that may help to neutralize invading pathogens and restore homeostasis. However, uncontrolled NET formation (NETosis) can result in numerous diseases that adversely affect health. Recent studies further elucidate the mechanistic details of the different forms of NETosis and their common end structure, as NETs were constantly found to contain DNA, modified histones and cytotoxic enzymes. In fact, emerging evidence reveal that the post translational modifications (PTMs) of histones in neutrophils have a critical role in regulating neutrophil death. Histone citrullination is shown to promote a rapid form of NET formation independent of NADPH oxidase (NOX), which relies on calcium influx. Interestingly, few studies suggest an association between histone citrullination and other types of PTMs to control cell survival and death, such as histone methylation. Even more exciting is the finding that histone acetylation has a biphasic effect upon NETosis, where histone deacetylase (HDAC) inhibitors promote baseline, NOX-dependent and -independent NETosis. However, increasing levels of histone acetylation suppresses NETosis, and to switch neutrophil death to apoptosis. Interestingly, in the presence of NETosis-promoting stimuli, high levels of HDACis limit both NETosis and apoptosis, and promote neutrophil survival. Recent studies also reveal the importance of the PTMs of neutrophils in influencing numerous pathologies. Histone modifications in NETs can act as a double-edged sword, as they are capable of altering multiple types of neutrophil death, and influencing numerous NET-mediated diseases, such as acute lung injury (ALI), thrombosis, sepsis, systemic lupus erythematosus, and cancer progression. A clear understanding of the role of different PTMs in neutrophils would be important for an understanding of the molecular mechanisms of NETosis, and to appropriately treat NETs-mediated diseases.

Post-Translational Protein Deimination Signatures in Serum and Serum-Extracellular Vesicles of Bos taurus Reveal Immune, Anti-Pathogenic, Anti-Viral, Metabolic and Cancer-Related Pathways for Deimination

“…Interestingly, a similar EV-mediated export of deiminated histones, as observed in cow serum-EVs in the current study, was recently identified in the naked mole-rat, an animal with unusual immunological and metabolic traits [98], as well as in alligator, also an animal with unusual antimicrobial, including anti-viral responses [93]. Deiminated histone H3 is commonly used as an indicator for neutrophil extracellular trap formation (NETosis) [31,244], which has been related to PAD4 and implicated in anti-viral responses in cattle respiratory syncytial virus disease [42], in response to parasitic infections in cattle [245][246][247] as well as in response to certain antibiotics [248]. Interestingly, in crocodilians, extracellular histones H2A and H4 have been identified to act as inhibitors of viral (HIV) infection in vitro [249], although roles for post-translational deimination were not assessed.…”

Neutrophil Extracellular Trap Induced Dendritic Cell Activation Leads to Th1 Polarization in Type 1 Diabetes

“…In this study we observed decreased levels of antimicrobial peptides, MPO and LL37 in T1D NETs and additionally uncovered a strong shift toward histone-associated DNA fragments compared to healthy NETs. Particular histone modifications are an increasingly recognized quality of NETs influencing both the process of NET release itself and NET effect on numerous diseases (39), and observed differences in NET composition in T1D patients might strongly influence their biological activity, including their contribution to T1D development and progression. Since NETs in general are a source of autoantigens (40) they may contain islet autoantigens in T1D patients, which in turn would be processed by dendritic cells and further elicit both specific B cell and T cell responses (41).…”

Orchestration of Neutrophil Extracellular Traps (Nets), a Unique Innate Immune Function during Chronic Obstructive Pulmonary Disease (COPD) Development

“…When neutrophils are stimulated by NETotic inducers such as lipopolysaccharide (LPS) or polymethylmethacrylate (PMA), Nox-dependent NET formation is induced [ 137 ]. Studies have reported that these agonists (LPS and PMA) induce Nox-dependent NET formation through two different mechanisms.…”

“…During NOX-derived ROS production optimal environment is created for NE and MPO [ 137 ]. These enzymes which are normally contained within azurophilic granules are now free to interact with the nucleus where they may cleave histones and facilitate chromatin decondensation [ 160 ].…”