Citrullinated histone H3, a marker of extracellular trap formation, is increased in blood of stable asthma patients

Abstract

Background: Emerging data indicates that extracellular traps (ETs), structures formed by various immune cell types, may contribute to the pathology of noninfectious inflammatory diseases. Histone hypercitrullination is an important step in ETs formation and citrullinated histone H3 (H3cit) is considered a novel and specific biomarker of that process. In the present study we have evaluated circulating H3cit in stable asthmatics and investigated its relationship with asthma severity, pulmonary function and selected blood and bronchoalveolar lavage (BAL) biomarkers. Methods: In 60 white adult stable asthmatics and 50 well-matched controls we measured serum levels of H3cit. In asthmatics we also performed bronchoscopy with BAL. We analyzed blood and BAL biomarkers, including interleukin (IL)-4, IL-5, IL-6, IL-10, IL-12p70, IL-17A and interferon γ. For statistical analysis, Mann-Whitney U-test, χ 2 test, one-way ANCOVA, ROC curve analysis and univariate linear regression were applied. Independent determinants of H3cit were established in a multiple linear regression model. Results: Asthma was characterized by elevated circulating H3cit (17.49 [11.25-22.58] vs. 13.66 [8.66-18.87] ng/ml, p = 0.03). In asthmatics positive associations were demonstrated between serum H3cit and lung function variables, including total lung capacity (TLC) (β = 0.37 [95% CI 0.24-0.50]) and residual volume (β = 0.38 [95% CI 0.25-0.51]). H3cit was increased in asthma patients receiving systemic steroids (p = 0.02), as well as in subjects with BAL eosinophilia above 144 cells/ml (p = 0.02). In asthmatics, but not in controls, circulating H3cit correlated well with number of neutrophils (β = 0.31 [95% CI 0.19-0.44]) and monocytes (β = 0.42 [95% CI 0.29-0.55]) in peripheral blood. Furthermore, BAL macrophages, BAL neutrophils, TLC, high-sensitivity C-reactive protein, Il-12p70 and bronchial obstruction degree were independent determinants of H3cit in a multivariate linear regression model. Conclusions: Asthma is characterized by increased circulating H3cit likely related to the enhanced lung ETs formation. Inhibition of ETs might be a therapeutic option in selected asthma phenotypes, such as neutrophilic asthma.

Dengue Virus Envelope Protein Domain III Induces Nlrp3 Inflammasome-Dependent NETosis-Mediated Inflammation in Mice

“…Flow cytometry analysis of NETosis markers citrullinated histone H3 (CitH3) ( 53 , 54 ) and histone H2A family member X (H2AX) ( 55 , 56 ) revealed that rEIII is sufficient to initiate NETosis in neutrophils; the potency of rEIII is comparable to the classical NETosis inducer phorbol ester ( 18 , 57 ) ( Figure 1A , Supplementary Figure 1 , flow cytometry gating; Figure 1B ). In addition, such induction of NETosis can be suppressed by treatments of inflammasome/caspase 1 inhibitor Z-WHED-FMK ( Figure 1 ).…”

Role of Histone Post-Translational Modifications in Inflammatory Diseases

“…Inhibiting H3K27me3 demethylation by a selective inhibitor GSK-J4 could improve the typical hallmarks of asthma, including airway inflammation, hyperresponsiveness, and remodeling, then alleviate the development of asthmatic disease ( 155 ). A study showed an elevated circulating H3cit level in stable asthmatics which is related to the enhanced lung extracellular traps (ETs) ( 25 ).…”

Epigenetic Modifications in Tumor-Associated Macrophages: A New Perspective for an Old Foe

“…The level of citrullinated histone H3 significantly increases after LPS stimulation in macrophages derived from U937 cells in vitro , as a result of the enhanced expression level of peptidylarginine deiminases ( 121 ). The involvement of histone H3 citrullination in epigenetic regulation or gene expression has not been thoroughly studied, but it has been demonstrated to be an important step in the formation of extracellular traps for immune cells ( 122 ).…”