Aryl Hydrocarbon Receptor Defect Attenuates Mitogen-Activated Signaling Through Leucine-Rich Repeats and Immunoglobulin-Like Domains 1 (LRIG1)-Dependent EGFR Degradation

Aryl hydrocarbon receptor (AHR) genomic pathway has been well-characterized in a number of respiratory diseases. In addition, the cytoplasmic AHR protein may act as an adaptor of E3 ubiquitin ligase. In this study, the physiological functions of AHR that regulate cell proliferation were explored using the CRISPR/Cas9 system. The doubling-time of the AHR-KO clones of A549 and BEAS-2B was observed to be prolonged. The attenuation of proliferation potential was strongly associated with either the induction of p27Kip1 or the impairment in mitogenic signal transduction driven by the epidermal growth factor (EGF) and EGF receptor (EGFR). We found that the leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a repressor of EGFR, was induced in the absence of AHR in vitro and in vivo. The LRIG1 tends to degrade via a proteasome dependent manner by interacting with AHR in wild-type cells. Either LRIG1 or a disintegrin and metalloprotease 17 (ADAM17) were accumulated in AHR-defective cells, consequently accelerating the degradation of EGFR, and attenuating the response to mitogenic stimulation. We also affirmed low AHR but high LRIG1 levels in lung tissues of chronic obstructive pulmonary disease (COPD) patients. This might partially elucidate the sluggish tissue repairment and developing inflammation in COPD patients.

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Bactericidal/Permeability-Increasing Protein Preeminently Mediates Clearance of Pseudomonas aeruginosa In Vivo via CD18-Dependent Phagocytosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.659523 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jomkuan Theprungsirikul ◽

Sladjana Skopelja-Gardner ◽

Ashley S. Burns ◽

Rachel M. Wierzbicki ◽

William F. C. Rigby

Keyword(s):

Pseudomonas Aeruginosa ◽

Critical Role ◽

Chronic Obstructive ◽

Dependent Manner ◽

Opsonic Activity ◽

Obstructive Pulmonary Disease ◽

Neutrophil Dysfunction ◽

Chronic Lung Infection

Chronic Pseudomonas aeruginosa infection mysteriously occurs in the airways of patients with cystic fibrosis (CF), bronchiectasis (BE), and chronic obstructive pulmonary disease (COPD) in the absence of neutrophil dysfunction or neutropenia and is strongly associated with autoimmunity to bactericidal permeability-increasing protein (BPI). Here, we define a critical role for BPI in in vivo immunity against P. aeruginosa. Wild type and BPI-deficient (Bpi-/-) mice were infected with P. aeruginosa, and bacterial clearance, cell infiltrates, cytokine production, and in vivo phagocytosis were quantified. Bpi-/- mice exhibited a decreased ability to clear P. aeruginosa in vivo in concert with increased neutrophil counts and cytokine release. Bpi-/- neutrophils displayed decreased phagocytosis that was corrected by exogenous BPI in vitro. Exogenous BPI also enhanced clearance of P. aeruginosa in Bpi-/- mice in vivo by increasing P. aeruginosa uptake by neutrophils in a CD18-dependent manner. These data indicate that BPI plays an essential role in innate immunity against P. aeruginosa through its opsonic activity and suggest that perturbations in BPI levels or function may contribute to chronic lung infection with P. aeruginosa.

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Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

European Respiratory Journal ◽

10.1183/09031936.00215114 ◽

2015 ◽

Vol 46 (3) ◽

pp. 771-782 ◽

Cited By ~ 25

Author(s):

Antoine Guillon ◽

Youenn Jouan ◽

Deborah Brea ◽

Fabien Gueugnon ◽

Emilie Dalloneau ◽

...

Keyword(s):

Chronic Obstructive ◽

Dependent Lung ◽

Obstructive Pulmonary Disease ◽

Copd Exacerbations ◽

Interleukin 22 ◽

Copd Patients ◽

Acute Exacerbations ◽

Underlying Mechanisms

Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infection-driven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as β-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22-dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations.

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Streptococcus gallolyticus Increases Expression and Activity of Aryl Hydrocarbon Receptor-Dependent CYP1 Biotransformation Capacity in Colorectal Epithelial Cells

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.740704 ◽

2021 ◽

Vol 11 ◽

Author(s):

Rahwa Taddese ◽

Rian Roelofs ◽

Derk Draper ◽

Xinqun Wu ◽

Shaoguang Wu ◽

...

Keyword(s):

Epithelial Cells ◽

Aryl Hydrocarbon Receptor ◽

Specific Inhibitor ◽

Intestinal Bacteria ◽

Opportunistic Pathogen ◽

Dependent Manner ◽

Aryl Hydrocarbon ◽

Streptococcus Gallolyticus

ObjectiveThe opportunistic pathogen Streptococcus gallolyticus is one of the few intestinal bacteria that has been consistently linked to colorectal cancer (CRC). This study aimed to identify novel S. gallolyticus-induced pathways in colon epithelial cells that could further explain how S. gallolyticus contributes to CRC development.Design and ResultsTranscription profiling of in vitro cultured CRC cells that were exposed to S. gallolyticus revealed the specific induction of oxidoreductase pathways. Most prominently, CYP1A and ALDH1 genes that encode phase I biotransformation enzymes were responsible for the detoxification or bio-activation of toxic compounds. A common feature is that these enzymes are induced through the Aryl hydrocarbon receptor (AhR). Using the specific inhibitor CH223191, we showed that the induction of CYP1A was dependent on the AhR both in vitro using multiple CRC cell lines as in vivo using wild-type C57bl6 mice colonized with S. gallolyticus. Furthermore, we showed that CYP1 could also be induced by other intestinal bacteria and that a yet unidentified diffusible factor from the S. galloltyicus secretome (SGS) induces CYP1A enzyme activity in an AhR-dependent manner. Importantly, priming CRC cells with SGS increased the DNA damaging effect of the polycyclic aromatic hydrocarbon 3-methylcholanthrene.ConclusionThis study shows that gut bacteria have the potential to modulate the expression of biotransformation pathways in colonic epithelial cells in an AhR-dependent manner. This offers a novel theory on the contribution of intestinal bacteria to the etiology of CRC by modifying the capacity of intestinal epithelial or (pre-)cancerous cells to (de)toxify dietary components, which could alter intestinal susceptibility to DNA damaging events.

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Tiotropium Is Predicted to Be a Promising Drug for COVID-19 Through Transcriptome-Based Comprehensive Molecular Pathway Analysis

Viruses ◽

10.3390/v12070776 ◽

2020 ◽

Vol 12 (7) ◽

pp. 776 ◽

Cited By ~ 3

Author(s):

Keunsoo Kang ◽

Hoo Hyun Kim ◽

Yoonjung Choi

Keyword(s):

Drug Target ◽

Chronic Obstructive ◽

Data Set ◽

Obstructive Pulmonary Disease ◽

Replication Complex ◽

Protein Protein Interaction ◽

Copd Patients ◽

Pathologic Features

The coronavirus disease 2019 (COVID-19) outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects almost everyone in the world in many ways. We previously predicted antivirals (atazanavir, remdesivir and lopinavir/ritonavir) and non-antiviral drugs (tiotropium and rapamycin) that may inhibit the replication complex of SARS-CoV-2 using our molecular transformer–drug target interaction (MT–DTI) deep-learning-based drug–target affinity prediction model. In this study, we dissected molecular pathways upregulated in SARS-CoV-2-infected normal human bronchial epithelial (NHBE) cells by analyzing an RNA-seq data set with various bioinformatics approaches, such as gene ontology, protein–protein interaction-based network and gene set enrichment analyses. The results indicated that the SARS-CoV-2 infection strongly activates TNF and NFκB-signaling pathways through significant upregulation of the TNF, IL1B, IL6, IL8, NFKB1, NFKB2 and RELB genes. In addition to these pathways, lung fibrosis, keratinization/cornification, rheumatoid arthritis, and negative regulation of interferon-gamma production pathways were also significantly upregulated. We observed that these pathologic features of SARS-CoV-2 are similar to those observed in patients with chronic obstructive pulmonary disease (COPD). Intriguingly, tiotropium, as predicted by MT–DTI, is currently used as a therapeutic intervention in COPD patients. Treatment with tiotropium has been shown to improve pulmonary function by alleviating airway inflammation. Accordingly, a literature search summarized that tiotropium reduced expressions of IL1B, IL6, IL8, RELA, NFKB1 and TNF in vitro or in vivo, and many of them have been known to be deregulated in COPD patients. These results suggest that COVID-19 is similar to an acute mode of COPD caused by the SARS-CoV-2 infection, and therefore tiotropium may be effective for COVID-19 patients.

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MiR-195-5p inhibits the development of chronic obstructive pulmonary disease via targeting siglec1

Human & Experimental Toxicology ◽

10.1177/0960327120920923 ◽

2020 ◽

Vol 39 (10) ◽

pp. 1333-1344

Author(s):

S Li ◽

L Jiang ◽

Y Yang ◽

J Cao ◽

Q Zhang ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Inflammatory Cytokines ◽

Inflammatory Responses ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Copd Patients ◽

Pulmonary Macrophages ◽

Pro Inflammatory Cytokines

Chronic obstructive pulmonary disease (COPD), characterized by chronic inflammation, is a recognized global health crisis. Sialic acid-binding immunoglobulin-like lectin 1 (siglec1 or CD169), mainly expressed in macrophages and dendritic cells, is markedly upregulated after encountering pathogens or under acute/chronic inflammation conditions. However, it is rarely reported that whether siglec1 plays a role in the development of COPD. In this study, we found that siglec1 had higher expression in the lungs from COPD rats and in peripheral blood mononuclear cells (PBMCs) from COPD patients. Knockdown of siglec1 in vivo and in vitro dramatically decreased pro-inflammatory cytokines production in pulmonary macrophages and alleviated pulmonary inflammatory responses in COPD rats as well as inactivated nuclear factor kappa B (NF-κB) signaling. In addition, we identified a new microRNA, miR-195-5p, which has never explored in COPD, was lower expressed in COPD rats and PBMC of COPD patients, and could negatively modulate siglec1 expression in macrophages. Moreover, overexpression of miR-195-5p via miR-195-5p mimics in vitro and in vivo could significantly alleviate pro-inflammatory cytokines production in pulmonary macrophages and pulmonary inflammatory responses in COPD rats. Together, our findings suggested that miR-195-5p inhibited the development of COPD via targeting siglec1, which might become a therapeutic target to improve COPD.

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Dexamethasone Inhibits Synergistic Induction of PDE4B Expression by Roflumilast and Bacterium NTHi

International Journal of Molecular Sciences ◽

10.3390/ijms19113511 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3511 ◽

Cited By ~ 1

Author(s):

Byung-Cheol Lee ◽

Seiko Susuki-Miyata ◽

Chen Yan ◽

Jian-Dong Li

Keyword(s):

Lung Epithelial Cells ◽

Chronic Obstructive ◽

Nontypeable Haemophilus Influenzae ◽

Obstructive Pulmonary Disease ◽

Copd Patients ◽

Lung Epithelial ◽

Synergistic Induction ◽

Phosphodiesterase 4B

Phosphodiesterase 4B (PDE4B) plays an important role in inflammation. Recently we have reported that roflumilast as a PDE4-selective inhibitor, synergizes with nontypeable Haemophilus influenzae (NTHi) to up-regulate PDE4B expression in vitro and in vivo. Clinical evidence and our previous results suggest that synergistic induction of PDE4B could be counterproductive for suppressing inflammation or may contribute to tolerance to roflumilast. We thus investigated if dexamethasone inhibits the synergistic induction of PDE4B by roflumilast and NTHi as well as inflammation. Here, dexamethasone markedly suppressed the synergistic induction of PDE4B in human lung epithelial cells and in vivo. We also found that dexamethasone further suppressed NTHi-induced inflammatory response in vitro and in vivo. Moreover, Compound A, as a dissociating non-steroidal glucocorticoid receptor (GR) ligand, inhibited the synergistic induction of PDE4B, thereby suggesting the requirement of dexamethasone-mediated GR activation in the suppression of PDE4B expression. Taken together, our data suggest that dexamethasone may help attenuate inflammation and tolerance through suppressing the PDE4B expression in chronic obstructive pulmonary disease (COPD) patients using roflumilast.

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The Aryl Hydrocarbon Receptor (AhR) Mediates the Counter-Regulatory Effects of Pelargonidins in Models of Inflammation and Metabolic Dysfunctions

Nutrients ◽

10.3390/nu11081820 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1820 ◽

Cited By ~ 9

Author(s):

Michele Biagioli ◽

Adriana Carino ◽

Chiara Fiorucci ◽

Giannamaria Annunziato ◽

Silvia Marchianò ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Natural Compound ◽

Intestinal Inflammation ◽

Body Weight Gain ◽

Liver Steatosis ◽

Signs And Symptoms ◽

Dependent Manner ◽

Aryl Hydrocarbon

Pelargonidins are anthocyanidins thought to be beneficial for the human health, although controversies exist over the doses needed and the unclear mechanism of action, along with poor systemic bioavailability. One putative target of pelargonidins is the aryl hydrocarbon receptor (AhR). A synthetic pelargonidin (Mt-P) was synthesized by the methylation of the pelargonidin (the natural compound indicated as P). Mt-P transactivated the AhR with an EC50 of 1.97 µM and was ~2-fold more potent than the natural compound. In vitro Mt-P attenuated pro-inflammatory activities of Raw264.7 macrophage cells in an AhR-dependent manner. In vivo, administration of the Mt-P in Balb/c mice resulted in a dose-dependent attenuation of signs and symptoms of colitis induced by TNBS. A dose of 5 mg/kg Mt-P, but not the natural compound P, reversed intestinal inflammation and increased expression of Tnf-α, Ifn-ƴ, and Il-6, while promoted the expansion of regulatory T cells and M2 macrophages. In C57BL/6J mice fed a high fat diet (HFD), Mt-P attenuated body weight gain, intestinal and liver inflammation, and ameliorated insulin sensitivity, while worsened liver steatosis by up-regulating the liver expression of Cd36 and Apo100b. These effects were abrogated by AhR gene ablation. Mt-P is a synthetic pelargonidin endowed with robust AhR agonist activity that exerts beneficial effects in murine models of inflammation and metabolic dysfunction.

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Induction and regulation of murine emphysema by elastin peptides

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00068.2015 ◽

2016 ◽

Vol 310 (1) ◽

pp. L8-L23 ◽

Cited By ~ 11

Author(s):

Mehdi Sellami ◽

Aïda Meghraoui-Kheddar ◽

Christine Terryn ◽

Caroline Fichel ◽

Nicole Bouland ◽

...

Keyword(s):

Biological Activities ◽

Inflammatory Cells ◽

Binding Activity ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Docking Simulations ◽

Copd Patients ◽

Cell Accumulation

Emphysema is the major component of chronic obstructive pulmonary disease (COPD). During emphysema, elastin breakdown in the lung tissue originates from the release of large amounts of elastase by inflammatory cells. Elevated levels of elastin-derived peptides (EP) reflect massive pulmonary elastin breakdown in COPD patients. Only the EP containing the GXXPG conformational motif with a type VIII β-turn are elastin receptor ligands inducing biological activities. In addition, the COOH-terminal glycine residue of the GXXPG motif seems a prerequisite to the biological activity. In this study, we endotracheally instilled C57BL/6J mice with GXXPG EP and/or COOH-terminal glycine deleted-EP whose sequences were designed by molecular dynamics and docking simulations. We investigated their effect on all criteria associated with the progression of murine emphysema. Bronchoalveolar lavages were recovered to analyze cell profiles by flow cytometry and lungs were prepared to allow morphological and histological analysis by immunostaining and confocal microscopy. We observed that exposure of mice to EP elicited hallmark features of emphysema with inflammatory cell accumulation associated with increased matrix metalloproteinases and desmosine expression and of remodeling of parenchymal tissue. We also identified an inactive COOH-terminal glycine deleted-EP that retains its binding-activity to EBP and that is able to inhibit the in vitro and in vivo activities of emphysema-inducing EP. This study demonstrates that EP are key actors in the development of emphysema and that they represent pharmacological targets for an alternative treatment of emphysema based on the identification of EP analogous antagonists by molecular modeling studies.

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Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1418716112 ◽

2015 ◽

Vol 112 (14) ◽

pp. E1800-E1809 ◽

Cited By ~ 17

Author(s):

Seiko Susuki-Miyata ◽

Masanori Miyata ◽

Byung-Cheol Lee ◽

Haidong Xu ◽

Hirofumi Kai ◽

...

Keyword(s):

Cross Talk ◽

Nuclear Factor Κb ◽

Airway Epithelial Cells ◽

Pde4 Inhibitor ◽

Chronic Obstructive ◽

Dependent Manner ◽

Obstructive Pulmonary Disease ◽

Synergistic Induction

Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of PDE4B up-regulation, which could be counterproductive for suppressing inflammation. Thus, understanding how PDE4B is up-regulated in the context of the complex pathogenesis and medications of COPD may help improve the efficacy and possibly ameliorate the tolerance of roflumilast. Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae (NTHi), a major bacterial cause of COPD exacerbation, to up-regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo. Up-regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity-dependent and activity-independent manners. We also found that protein kinase A catalytic subunit β (PKA-Cβ) and nuclear factor-κB (NF-κB) p65 subunit were required for the synergistic induction of PDE4B2. PKA-Cβ phosphorylates p65 in a cAMP-dependent manner. Moreover, Ser276 of p65 is critical for mediating the PKA-Cβ–induced p65 phosphorylation and the synergistic induction of PDE4B2. Collectively, our data unveil a previously unidentified mechanism underlying synergistic up-regulation of PDE4B2 via a cross-talk between PKA-Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of PDE4 inhibitor.

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MTMR14 Alleviates Chronic Obstructive Pulmonary Disease as a Regulator in Inflammation and Emphysema

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/9300269 ◽

2022 ◽

Vol 2022 ◽

pp. 1-21

Author(s):

Yiya Gu ◽

Jinkun Chen ◽

Qian Huang ◽

Yuan Zhan ◽

Ting Wang ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Mitochondrial Function ◽

Lavage Fluid ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Copd Patients

Extensive inflammation and apoptosis in structural cells of the lung are responsible for the progression and pathogenesis of chronic obstructive pulmonary disease (COPD). Myotubularin-related protein 14 (MTMR14) has been shown to participate in various biological processes, including apoptosis, inflammation, and autophagy. Nonetheless, the role of MTMR14 in COPD remains elusive. In the present study, we explored the expression of MTMR14 in human lung tissues and investigated the effects of overexpressed MTMR14 on in vitro and in vivo COPD models. Moreover, one of the possible mechanisms of MTMR14 alleviating COPD was explored based on mitochondrial function and mitophagy homeostasis. The results showed that MTMR14 expression was reduced in COPD patients’ lungs in comparison to control subjects. MTMR14 overexpression inhibited cigarette smoke extract-induced inflammation and apoptosis and improved mitochondrial function and mitophagy in vitro. Further verification was carried out in COPD model mice. MTMR14 overexpression inhibited lung inflammation and reduced levels of IL-6 and KC in bronchoalveolar lavage fluid, as well as prevented emphysema and a decline in lung function. Furthermore, MTMR14 overexpression improved mitochondrial function and mitophagy to a certain extent. Collectively, our data support the hypothesis that MTMR14 participates in the pathogenesis of COPD. Improving mitochondrial function and mitophagy homeostasis may be one of the mechanisms by which MTMR14 alleviates COPD and may potentially be a novel therapeutic target for COPD.

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