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.
Highlights
The multicellular structure of the human body depends heavily on the innate immune system in the event of microbial infection
Histone modifications in neutrophil extracellular traps (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
Histone acetylation is the transfer of an acetyl group from acetyl-CoA to histone lysine residue via a nucleophilic addition/elimination reaction which is catalyzed by histone acetyltransferase (HAT), which is grouped into 2 classes: A-type and B-type HATs [12]
Summary
The multicellular structure of the human body depends heavily on the innate immune system in the event of microbial infection. As neutrophils constitute the major components of the innate immunity, they are the first to respond against a large range of pathogens, such as bacteria and fungi [1]. They can be problematic in circulation or in tissues, depending on the intensity of the neutrophil influx. By using histone deacetylase inhibitors (HDACis) to promote AcH4 levels, a dose-dependent switch of neutrophil death from NETosis to apoptosis was reported [7]. We will discuss the impact of histone modifications during NET-mediated diseases
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