Epithelium-derived IL17A Promotes Cigarette Smoke–induced Inflammation and Mucus Hyperproduction

Wu, Mindan; Lai, Tianwen; Du, Jing; Yang, Shi-Yi; Wu, Yanping; Li, Zhouyang; Wu, Yangjie; Zhao, Yun; Zhou, Lingren; Chen, Haipin; Shen, Jiawei; Li, Wen; Ying, Songmin; Chen, Zhihua; Wu, Xiaohong; Shen, Huahao

doi:10.1165/rcmb.2020-0424oc

Cited by 32 publications

(22 citation statements)

References 39 publications

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“…To further evaluate the impact of WNT/β-catenin signaling pathway during acute airway inflammation and stable COPD, we applied two different animal models, CE and CS exposure, respectively. The CE model has been demonstrated with much higher levels of neutrophilic airway inflammation, mucus hyperproduction, and predominant Th17 response than traditional CS model, somehow mimicking the bronchitis phenotype or AECOPD [ 6 , 24 , 25 ]. The down-regulation of WNT/β-catenin signaling pathway was observed in both animal models, which emphasized that the decreased activity of WNT/β-catenin pathway was not only involved in the progression of COPD but might also be associated with the onset of acute exacerbation.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease

Wang

Zhong

et al. 2022

Respir Res

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Background Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the main factor that leads to the deterioration of the disease. Currently, the diagnosis of AECOPD mainly relies on clinical manifestations, good predictors or biomarkers are lacking. We aim to reveal specific biomarkers and potential pathogenesis of AECOPD and provide a research basis for the diagnosis and treatment. Methods Four patients with AECOPD, four patients with stable COPD, and five control subjects were enrolled for RNA sequencing and KEGG analysis. The mRNA level of target genes was verified by quantitative real-time PCR (qPCR) with an expanded sample size (30 patients with AECOPD, 27 patients with stable COPD, and 35 control subjects). ELISA and immunofluorescence were used to identify the target proteins. Furthermore, the expression and function of WNT/β-catenin signaling pathway were assessed in animal models of COPD. Results RNA sequencing showed that 54 genes were up-regulated and 111 genes were down-regulated in the AECOPD. Differentially expressed genes were mainly enriched in WNT signaling pathway, et al. QPCR revealed that multi-genes of the WNT/β-catenin signaling were significantly down-regulated in AECOPD (P < 0.05), and β-catenin protein was significantly decreased in plasma of AECOPD and stable COPD (P < 0.01), while phosphorylated β-catenin was significantly up-regulated in peripheral blood mononuclear cells of AECOPD (P < 0.05). Similarly, WNT ligands, WNT receptors, and downstream signaling molecules were down-regulated, with an increased phosphorylated β-catenin protein in animal models of COPD. Activation of WNT/β-catenin signaling pathway by lithium chloride reduced the expression of phosphorylated β-catenin and ameliorated the COPD-like airway inflammation in mice. Conclusion WNT/β-catenin signaling pathway is down-regulated in AECOPD patients and in animal models of COPD. Increased expression of phosphorylated β-catenin in the blood might be a potential biomarker of AECOPD. Activation of WNT/β-catenin pathway may also represent a therapeutic target for AECOPD.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease

Wang

Zhong

et al. 2022

Respir Res

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“…Mucus overproduction is a major risk factor for asthma morbidity and mortality ( 1 ). While evidence has shown that Muc5ac overexpression leads to the development of airway mucus plugging, AHR, and asthma exacerbations ( 7 – 10 ), the mechanisms underlying development and immune regulation of mucus production in response to allergens are not fully unveiled. In the current study, we found that cockroach allergen exposure can induce Muc5ac over expression and provided evidence that epithelial AhR is required in protecting against cockroach allergen-induced Muc5ac expression and airway inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Muc5ac secreted by the goblet cells within epithelium is the predominant mucin glycoprotein implicated in fatal asthmatic airway mucus plugging ( 1 , 3 , 7 ). Muc5ac over-expression has been associated with the development of airway mucus plugging, allergic airway hyper-reactivity, and progressive loss of lung function, and asthma exacerbations ( 7 – 10 ). A very recent finding from a multicenter, observational study suggests that increased Muc5ac concentration in induced sputum was a major driver in COPD initiation, progression, exacerbation risk, and overall pathogenesis ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma

Shen

Zhao

et al. 2021

Front. Immunol.

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BackgroundDespite long-standing recognition in the significance of mucus overproduction in asthma, its etiology remains poorly understood. Muc5ac is a secretory mucin that has been associated with reduced pulmonary function and asthma exacerbations.ObjectivesWe sought to investigate the immunological pathway that controls Muc5ac expression and allergic airway inflammation in asthma.MethodsCockroach allergen-induced Muc5ac expression and aryl hydrocarbon receptor (AhR) signaling activation was examined in the human bronchial epithelial cells (HBECs) and mouse model of asthma. AhR regulation of Muc5ac expression, mitochondrial ROS (Mito-ROS) generation, and NLRP3 inflammasome was determined by AhR knockdown, the antagonist CH223191, and AhR-/- mice. The role of NLRP3 inflammasome in Muc5ac expression and airway inflammation was also investigated.ResultsCockroach allergen induced Muc5ac overexpression in HBECs and airways of asthma mouse model. Increased expression of AhR and its downstream genes CYP1A1 and CYP1B1 was also observed. Mice with AhR deletion showed increased allergic airway inflammation and MUC5AC expression. Moreover, cockroach allergen induced epithelial NLRP3 inflammasome activation (e.g., NLRP3, Caspase-1, and IL-1β), which was enhanced by AhR knockdown or the antagonist CH223191. Furthermore, AhR deletion in HBECs led to enhanced ROS generation, particularly Mito-ROS, and inhibition of ROS or Mito-ROS subsequently suppressed the inflammasome activation. Importantly, inhibition of the inflammasome with MCC950, a NLRP3-specifc inhibitor, attenuated allergic airway inflammation and Muc5ac expression. IL-1β generated by the activated inflammasomes mediated cockroach allergen-induced Muc5ac expression in HBECs.ConclusionsThese results reveal a previously unidentified functional axis of AhR-ROS-NLRP3 inflammasome in regulating Muc5ac expression and airway inflammation.

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Section: Discussionmentioning

confidence: 99%

“…Muc5ac secreted by the goblet cells within epithelium is the predominant mucin glycoprotein implicated in fatal asthmatic airway mucus plugging (1,3,7). Muc5ac overexpression has been associated with the development of airway mucus plugging, allergic airway hyper-reactivity, and progressive loss of lung function, and asthma exacerbations (7)(8)(9)(10). A very recent finding from a multicenter, observational study suggests that increased Muc5ac concentration in induced sputum was a major driver in COPD initiation, progression, exacerbation risk, and overall pathogenesis (11).…”

Section: Introductionmentioning

confidence: 99%

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Epithelium-derived IL17A Promotes Cigarette Smoke–induced Inflammation and Mucus Hyperproduction

Cited by 32 publications

References 39 publications

Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease

Transcriptomic analysis and validation reveal the pathogenesis and a novel biomarker of acute exacerbation of chronic obstructive pulmonary disease

Epithelial Aryl Hydrocarbon Receptor Protects From Mucus Production by Inhibiting ROS-Triggered NLRP3 Inflammasome in Asthma

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