The Molecular Mechanisms Of HDAC2 And IL-17A In COPD And Asthma

Chronic obstructive pulmonary disease(COPD)and bronchial asthma are the most common chronic inflammatory diseases of the airways.WHO showed that the global COPD patients have more than 230 million worldwide,and the mortality rate is increasing year by year,and is expected that COPD will become the world’s third largest cause of death in 2020.Currently,China has about 45 million COPD patients,COPD has become the fourth cause of death in the city,the first cause of death in rural areas.There are about 300 million asthma patients worldwide.It is about 30 million of patients with asthma in China,COPD and asthma seriously affect the quality of life of patients and it cuases a huge economic burden for patients,families,and society.Therefore,it is urgent to study the pathogenesis and effective treatment for COPD and asthma.COPD is a preventable and treatable chronic airway inflammation and airflow limitation disease development process with not completely reversible.Smoking is the most important predisposing factor for COPD,but its pathogenesis has not been elucidated.The main airway inflammation of COPD includes Thl and TC1 type immune response,neutrophils,macrophages and CD8+ T cells,and mucus hypersecretion and mucociliary clearance disfunction.More and more evidences show that the pathogenesis of COPD is closely related to the immune response.Many studies showed that COPD patients were insensitive to corticosteroid therapy.Inhaled corticosteroids(ICS)therapies have no effect on the inflammatory cells and proinflammatory mediators’ production in COPD.At present,there is still a lack of effective prevention and control measures for COPD.It is generally believed that the pathogenesis of asthma mainly involves the immune imbalance of Th1/Th2 cell,Asthma is a chronic inflammatory airway disease and inflammatory cytokines mainly includes eosinophils,mast cells and T lymphocytes and other inflammatory cells.Asthma is characterized with airway mucus hypersecretion,airway hyperresponsiveness and airway remodeling.ICS is one of the most effective methods for the treatment of asthma.ICS treatment is effective for most of the asthmatic patients with eosinophilic airway inflammation.However,some studies have shown that ICS treatment has no effect on some asthmatic patients with neutrophilic airway inflammation and most of these patients were severe asthma.The inflammatory characteristics in severe asthma were different from those of mild asthma,but similar to COPD.Clinical studies have shown that levels and activity of histone deacetylase 2(HDAC2)were significantly reduced in patients with COPD and severe asthma,and may be an important factor in corticosteroid insensitivity in these patients with chronic airway inflammation.Recent studies have shown that neutrophil response to chronic airway inflammation is closely related with Th17 cells.Th17 cells are a new class of effector CD4 T cells that secrete IL-17A-F and IL-22 cytokines.The level of IL-17A in patients with severe asthma was higter than that in patients with mild to moderate asthma and airway neutrophil number was positively correlated with diseas severtiy.The expression of Th17-associated inflammatory cytokines were increased in airway of patients with COPD.These studies suggest that Th17 cells play an important role in the molecular pathogenesis of neutrophil airway inflammation.The early differentiation of Th17 depends on the combination of IL-1 signaling pathway and IL-6.In chronic airway inflammation,the production of these inflammatory factors may be related to HDAC2.The dynamic balance between HDAC and histone acetyltransferase(HAT)controls the acetylation of histones and the structure of chromatin,regulates the expression of various inflammatory genes from the molecular transcriptional level,and plays an important role in chronic airway inflammation.The decrease of HDAC2 activity increased the acetylation level of histone,leading to the increase of transcription factor activity,such as NF-κB,and the expression of IL-6 and pro-IL-1β.We hypothesize that HDAC2 regulates the production of inflammatory factors such as IL-1β and IL-6,and regulates Th17 differentiation and neutrophil airway inflammatory response,which may be related to the regulation of HDAC2 and IL-17A,and paly an important role in the molecular pathogenesis of COPD and severe asthma.In this study,we aimed to investigate the mechanism of HDAC2 and IL-17A regulation in airway remodeling and airway inflammation in COPD and asthma.We collected human samples included COPD and asthma patients.COPD and asthmatic models were established by using HDAC2 and IL-17A knockout mice.In vitro,the effects of HDAC2 and IL-17A on the expression of HDAC2 and IL-17A in airway epithelial cells and lung fibroblasts were studied.Part Ⅰ Histone deacetylase 2 suppresses IL17A-mediated airway remodeling in COPDBackground:Airway remodeling is a central feature of chronic obstructive pulmonary disease(COPD);However,the mechanisms underlying its development have not been fully elucidated.Objective:To determine whether histone deacetylase(HDAC)2 protects against cigarette smoke(CS)-induced airway remodeling through IL17A-dependent mechanisms.Methods:The study protocols included sputum induction for inflammatory biomarkers,high-resolution computed tomography(HRCT)of the lungs to identify bronchial wall thickening,and isolation of human primary fibroblasts.In parallel,transgenic mice were used in a model of CS-induced airway remodeling.Results:HDAC2 and IL17A expression in the sputum and lung tissues of patients with COPD were associated with bronchial wall thickening and collagen deposition around the airways.Il17a deficiency {il17a-/-)resulted in attenuation of,whereas Hdac2 deficiency(Hdac2+/-)exacerbated,CS-induced airway remodeling in mice.Interestingly,HDAC2 suppressed IL17A production in part through the activation of CD4+ T cells during Th17 cells differentiation and retinoid-related orphan nuclear receptor yt(RORyt)in airway epithelial cells.Additional IL17A deletion(Hdac2/il17a double-deficient mice)reduced airway remodeling in CS-exposed Hdac2+/-mice by suppressing airway inflammation and modulating fibroblast activation.In vitro,IL17A promoted the collagen deposition of human primary fibroblasts through an autocrine production of transforming growth factor β1.Conclusion:Collectively,these findings underscore the importance of IL17A as a mediator in the beneficial effect of HDAC2 on airway remodeling by suppressing airway inflammation and modulating fibroblast activation.Thus,activation of HDAC2 and/or inhibition of IL17A production may serve as therapeutic strategies for airway remodeling in COPD.Part Ⅱ HDAC2-IL17A axis sets up a vicious regulatory circle in asthmaBackgroud and Objective:Decreased histone deacetylase(HDAC)2 production has been associated with more severe asthma;However,it is not known how HDAC2 regulates airway inflammation and whether interleukin(IL)17A can contribute to HDAC2-mediated pathology in asthmatic patients remain unclear.To elucidate the role of HDAC2 in house dust mite(HDM)-induced airway inflammation,focusing on its interaction with IL17A.Methods:The relationship between HDAC2 and IL17A in biopsy tissues from asthmatic patients and mice was assessed.In parallel,transgenic mice were used in a model of HDM-induced asthma.In vitro,the interaction between HDAC2 and IL17A in HDM-stimulated human bronchial epithelial(HBE)cells was investigated.Results:HDAC2 expression was negatively associated with IL17A levels in biopsy tissues from asthmatic patients.HDM exposure induced an increased airway inflammation and ILI7A expression in Hdac2+/-mice.In contrast,HDM-exposed Il17a-/-mice displayed reduced airway inflammation and increased the nuclear levels of HDAC2.Intriguingly,HDM-exposed Hdac2/Il17a double-deficient mice showed that additional IL17A deletion greatly improved airway inflammation in HDM-exposed Hdac2+/-mice.In vitro,stimulation with HDM and/or IL17A decreased HDAC2 expression in HBE cells,and knockdown of IL17A attenuated HDM-induced reduction of HDAC2.On the other hand,silencing of Hdac2 gene significantly increased expression of cytokines in HDM-induced HBE cells.In contrast,silencing of IL17A gene significantly decreased expression of cytokines.Conclusion:HDM resulted in HDAC2 reduction,which promoted asthma airway inflammation.HDAC2 reduction promoted IL-17A secretion by regulating CD4+ T andγδ T cell differentiation,and further deterioration of asthma airway inflammation.In contrast,IL-17A gene knockout attenuated asthma airway inflammation caused by HDAC2 reduction.There was a mechanism of mutual regulation between HDAC2 and IL-17A.HDAC2 attenuated HDM-induced asthma airway inflammation may via inhibit IL-17A secretion in airway epithelial cells.These findings open a new option that HDAC2-IL17A axis sets up a vicious regulatory circle,thereby playing a critical role in the amplification of allergic airway inflammation,and targeting HDAC2-IL-17A signaling pathway may be effective in relieving asthma airway inflammation and mucus secretion,especially in IL17A-mediated asthmatic patients.