Histone Acetylation Promotes Neutrophil Extracellular Trap Formation

Hamam, Hussein J.; Khan, Meraj A.; Palaniyar, Nades

doi:10.3390/biom9010032

Cited by 80 publications

(71 citation statements)

References 36 publications

(66 reference statements)

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“…We have recently shown than neutrophils treated with lower concentrations of HDACis lead to increased levels of histone acetylation, chromatin relaxation and NETosis [12,21,22]. Therefore, we questioned whether increasing concentrations of HDACis have the potential to further promote histone acetylation in neutrophils.…”

Section: Resultsmentioning

confidence: 99%

“…Citrullination of histone H3 (CitH3) results in histone relaxation and was considered as a hallmark of NOX-independent NETosis [11]. We have recently shown that another epigenetic modification—histone acetylation (e.g., acetylated histone H4, AcH4)—promotes both types of NET formation [12]. Due to the loss of positively charged lysine, AcH4 results in increased levels of histone decondensation and gene transcription which eventually promoted NETosis by ~20% without altering intracellular ROS production by either NOX or mitochondria.…”

Section: Introductionmentioning

confidence: 99%

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Histone Deacetylase Inhibitors Dose-Dependently Switch Neutrophil Death from NETosis to Apoptosis

Hamam

Palaniyar

2019

Biomolecules

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Acetylation is an important post translational modification of histone that plays a role in regulation of physiological and pathological process in the body. We have recently shown that the inhibition of histone deacetylases (HDAC) by low concentrations of HDAC inhibitors (HDACis), belinostat (up to 0.25 µM) and panobinostat (up to 0.04 µM) promote histone acetylation (e.g., AcH4) and neutrophil extracellular trap formation (NETosis). Clinical use of belinostat and panobinostat often leads to neutropenia and the in vivo concentrations vary with time and tissue locations. However, the effects of different concentrations of these HDACis on neutrophil death are not fully understood. We considered that increasing concentrations of belinostat and panobinostat could alter the type of neutrophil death. To test this hypothesis, we treated human neutrophils with belinostat and panobinostat in the presence or absence of agonists that promote NOX-dependent NETosis (phorbol myristate acetate or lipopolysaccharide from Escherichia coli 0128) and NOX-independent NETosis (calcium ionophores A23187 or ionomycin from Streptomyces conglobatus). Increasing concentrations of HDACis induced histone acetylation in a dose-dependent manner. ROS analyses showed that increasing concentrations of HDACis, increased the degree of NOX-derived ROS production. Higher levels (>1 µM belinostat and >0.2 µM panobinostat) of AcH4 resulted in a significant inhibition of spontaneous as well as the NOX-dependent and -independent NETosis. By contrast, the degree of neutrophil apoptosis significantly increased, particularly in non-activated cells. Collectively, this study establishes that increasing concentrations of belinostat and panobinostat initially increases NETosis but subsequently reduces NETosis or switches the form of cell death to apoptosis. This new information indicates that belinostat and panobinostat can induce different types of neutrophil death and may induce neutropenia and regulate inflammation at different concentrations.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Dose-Dependently Switch Neutrophil Death from NETosis to Apoptosis

Hamam

Palaniyar

2019

Biomolecules

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“…Another antimicrobial mechanism involves the release of histone-bound DNA complexed with primary granule proteins, such as NE and myeloperoxidase (MPO), in the form of NETs [72]. Formation of NETs is regulated by a complex pathway requiring histone citrullination by peptidyl arginine deiminase 4 (PAD4) followed by decondensation of the chromatin [73], which has more recently been shown to be promoted by histone acetylation using broadly acting inhibitors of histone deacetylase [74]. Mechanisms independent of PAD4 have also been described [75,76].…”

Section: Bacterial Infectionsmentioning

confidence: 99%

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Giacalone

Margaroli

Mall

et al. 2020

IJMS

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Neutrophils have a prominent role in all human immune responses against any type of pathogen or stimulus. The lungs are a major neutrophil reservoir and neutrophilic inflammation is a primary response to both infectious and non-infectious challenges. While neutrophils are well known for their essential role in clearance of bacteria, they are also equipped with specific mechanisms to counter viruses and fungi. When these defense mechanisms become aberrantly activated in the absence of infection, this commonly results in debilitating chronic lung inflammation. Clearance of bacteria by phagocytosis is the hallmark role of neutrophils and has been studied extensively. New studies on neutrophil biology have revealed that this leukocyte subset is highly adaptable and fulfills diverse roles. Of special interest is how these adaptations can impact the outcome of an immune response in the lungs due to their potent capacity for clearing infection and causing damage to host tissue. The adaptability of neutrophils and their propensity to influence the outcome of immune responses implicates them as a much-needed target of future immunomodulatory therapies. This review highlights the recent advances elucidating the mechanisms of neutrophilic inflammation, with a focus on the lung environment due to the immense and growing public health burden of chronic lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), and acute lung inflammatory diseases such as transfusion-related acute lung injury (TRALI).

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“…In response to certain infectious agents, neutrophils can expel their cellular DNA coated with antimicrobial granular proteins to the extracellular environment. The key events of NETosis include elevated intracellular calcium, ROS production (by NADPH oxidase; NOX and/or mitochondria), kinase activation (e.g., ERK, p38, JNK, Src, Akt, etc), DNA decondensation (via histone-3 citrullination, acetylation, and transcriptional firing), and eventual NET release [30,127,161,162,163,164,165]. The net-like structure is excellent for capturing microorganisms, including bacteria, fungi, and viruses [135,166,167,168].…”

Section: Neutrophil Anti-microbial Propertiesmentioning

confidence: 99%

Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation

Khan

Ali

Sweezey

et al. 2019

Genes

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Genetic defects in cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene cause CF. Infants with CFTR mutations show a peribronchial neutrophil infiltration prior to the establishment of infection in their lung. The inflammatory response progressively increases in children that include both upper and lower airways. Infectious and inflammatory response leads to an increase in mucus viscosity and mucus plugging of small and medium-size bronchioles. Eventually, neutrophils chronically infiltrate the airways with biofilm or chronic bacterial infection. Perpetual infection and airway inflammation destroy the lungs, which leads to increased morbidity and eventual mortality in most of the patients with CF. Studies have now established that neutrophil cytotoxins, extracellular DNA, and neutrophil extracellular traps (NETs) are associated with increased mucus clogging and lung injury in CF. In addition to opportunistic pathogens, various aspects of the CF airway milieux (e.g., airway pH, salt concentration, and neutrophil phenotypes) influence the NETotic capacity of neutrophils. CF airway milieu may promote the survival of neutrophils and eventual pro-inflammatory aberrant NETosis, rather than the anti-inflammatory apoptotic death in these cells. Degrading NETs helps to manage CF airway disease; since DNAse treatment release cytotoxins from the NETs, further improvements are needed to degrade NETs with maximal positive effects. Neutrophil-T cell interactions may be important in regulating viral infection-mediated pulmonary exacerbations in patients with bacterial infections. Therefore, clarifying the role of neutrophils and NETs in CF lung disease and identifying therapies that preserve the positive effects of neutrophils, while reducing the detrimental effects of NETs and cytotoxic components, are essential in achieving innovative therapeutic advances.

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Histone Acetylation Promotes Neutrophil Extracellular Trap Formation

Cited by 80 publications

References 36 publications

Histone Deacetylase Inhibitors Dose-Dependently Switch Neutrophil Death from NETosis to Apoptosis

Histone Deacetylase Inhibitors Dose-Dependently Switch Neutrophil Death from NETosis to Apoptosis

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation

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