FOXO3a regulates rhinovirus-induced innate immune responses in airway epithelial cells

AbstractForkhead transcription factor class O (FOXO)3a, which plays a critical role in a wide variety of cellular processes, was also found to regulate cell-type-specific antiviral responses. Airway epithelial cells express FOXO3a and play an important role in clearing rhinovirus (RV) by mounting antiviral type I and type III interferon (IFN) responses. To elucidate the role of FOXO3a in regulating antiviral responses, we generated airway epithelial cell-specific Foxo3a knockout (Scga1b1-Foxo3a−/−) mice and a stable FOXO3a knockout human airway epithelial cell line. Compared to wild-type, Scga1b1-Foxo3a−/− mice show reduced IFN-α, IFN-β, IFN-λ2/3 in response to challenge with RV or double-stranded (ds)RNA mimic, Poly Inosinic-polycytidylic acid (Poly I:C) indicating defective dsRNA receptor signaling. RV-infected Scga1b1-Foxo3a−/− mice also show viral persistence, enhanced lung inflammation and elevated pro-inflammatory cytokine levels. FOXO3a K/O airway epithelial cells show attenuated IFN responses to RV infection and this was associated with conformational change in mitochondrial antiviral signaling protein (MAVS) but not with a reduction in the expression of dsRNA receptors under unstimulated conditions. Pretreatment with MitoTEMPO, a mitochondrial-specific antioxidant corrects MAVS conformation and restores antiviral IFN responses to subsequent RV infection in FOXO3a K/O cells. Inhibition of oxidative stress also reduces pro-inflammatory cytokine responses to RV in FOXO3a K/O cells. Together, our results indicate that FOXO3a plays a critical role in regulating antiviral responses as well as limiting pro-inflammatory cytokine expression. Based on these results, we conclude that FOXO3a contributes to optimal viral clearance and prevents excessive lung inflammation following RV infection.

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MicroRNA-150 protects against cigarette smoke-induced lung inflammation and airway epithelial cell apoptosis through repressing p53: MicroRNA-150 in CS-induced lung inflammation

Human & Experimental Toxicology ◽

10.1177/0960327117741749 ◽

2017 ◽

Vol 37 (9) ◽

pp. 920-928 ◽

Cited By ~ 9

Author(s):

H Xue ◽

MX Li

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Cigarette Smoke ◽

Cell Apoptosis ◽

Lung Inflammation ◽

Airway Epithelial Cell ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

P53 Expression ◽

Epithelial Cell Apoptosis

Cigarette smoke (CS) exposure is an important risk factor for chronic obstructive pulmonary disease (COPD). MicroRNA-150 (miR-150) is involved in several inflammatory diseases. However, little is known about the role of miR-150 in the pathogenesis of COPD. In this study, we established a CS-related mouse model of COPD and evaluated the impact of miR-150 on CS-induced lung inflammation. We further investigated the effects of miR-150 overexpression on pro-inflammatory cytokine production and apoptosis in airway epithelial cells exposed to CS extract (CSE). It was found that miR-150 was significantly ( p < 0.05) downregulated in the lungs of CS-exposed mice, compared to control mice under normal air. The CSE-exposed BEAS-2B airway epithelial cells displayed a four- to six-fold reduction in miR-150 levels, compared to control cells ( p < 0.05). Delivery of miR-150 mimic attenuated CS-induced lung inflammation and accumulation of neutrophils, lymphocytes, and macrophages in bronchoalveolar lavage fluid. Moreover, miR-150 overexpression prevented the induction of interleukin-6, tumor necrosis factor alpha, and interleukin-8 expression and nuclear factor kappa B (NF-κB) transcriptional activity in BEAS-2B cells by CSE. Additionally, miR-150 protected BEAS-2B cells from CSE-induced apoptosis, which was associated with reduced p53 expression. Co-expression of p53 restored apoptotic response to CSE in miR-150-overexpressing BEAS-2B cells. Collectively, miR-150 suppresses CS-induced lung inflammation and airway epithelial cell apoptosis, which is causally linked to repression of p53 expression and NF-κB activity. Restoration of miR-150 expression may represent a potential therapeutic strategy for CS-related COPD.

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Paraoxonase-2 deficiency enhancesPseudomonas aeruginosaquorum sensing in murine tracheal epithelia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00370.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. L852-L860 ◽

Cited By ~ 94

Author(s):

David A. Stoltz ◽

Egon A. Ozer ◽

Carey J. Ng ◽

Janet M. Yu ◽

Srinivasa T. Reddy ◽

...

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Quorum Sensing ◽

Airway Epithelial Cell ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Airway Epithelia ◽

Tracheal Epithelial Cells ◽

Human Airway ◽

Tracheal Epithelial

Pseudomonas aeruginosa is an important cause of nosocomial infections and is frequently present in the airways of cystic fibrosis patients. Quorum sensing mediates P. aeruginosa's virulence and biofilm formation through density-dependent interbacterial signaling with autoinducers. N-3-oxododecanoyl homoserine lactone (3OC12-HSL) is the major autoinducer in P. aeruginosa. We have previously shown that human airway epithelia and paraoxonases (PONs) degrade 3OC12-HSL. This study investigated the role of PON1, PON2, and PON3 in airway epithelial cell inactivation of 3OC12-HSL. All three PONs were present in murine tracheal epithelial cells, with PON2 and PON3 expressed at the highest levels. Lysates of tracheal epithelial cells from PON2, but not PON1 or PON3, knockout mice had impaired 3OC12-HSL inactivation compared with wild-type mice. In contrast, PON1-, PON2-, or PON3-targeted deletions did not affect 3OC12-HSL degradation by intact epithelia. Overexpression of PON2 enhanced 3OC12-HSL degradation by human airway epithelial cell lysates but not by intact epithelia. Finally, using a quorum-sensing reporter strain of P. aeruginosa, we found that quorum sensing was enhanced in PON2-deficient airway epithelia. In summary, these results show that loss of PON2 impairs 3OC12-HSL degradation by airway epithelial cells and suggests that diffusion of 3OC12-HSL into the airway cells can be the rate-limiting step for degradation of the molecule.

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Hog barn dust extract augments lymphocyte adhesion to human airway epithelial cells

Journal of Applied Physiology ◽

10.1152/japplphysiol.00384.2003 ◽

2004 ◽

Vol 96 (5) ◽

pp. 1738-1744 ◽

Cited By ~ 22

Author(s):

T. Mathisen ◽

S. G. Von Essen ◽

T. A. Wyatt ◽

D. J. Romberger

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Cell Function ◽

Airway Epithelial Cell ◽

Airway Epithelial Cells ◽

Intercellular Adhesion Molecule ◽

Airway Epithelial ◽

Intercellular Adhesion Molecule 1 ◽

Lymphocyte Adhesion ◽

Dust Extract

The dust of hog confinement facilities induces airway inflammation. Mechanisms by which this dust modulates inflammation are not completely defined, although it is clear that exposure to dust can modulate both epithelial cell and inflammatory cell function. In this work, we demonstrate that airway epithelial cell (BEAS-2B) treatment with hog barn dust extract (HDE) results in augmentation of peripheral blood lymphocyte adhesion to epithelial cell cultures in vitro. The augmentation of lymphocyte adhesion to epithelial cells is dependent on the concentration of HDE and time of HDE exposure, with twofold increases observed by 3 h and maintained at 24 h. Similar results are seen with primary human bronchial epithelial cells in culture. Lymphocyte adhesion to epithelial cells is inhibited in a concentration-dependent fashion by the treatment of epithelial cells with antibody to intercellular adhesion molecule-1 (ICAM-1). In addition, HDE exposure of epithelial cells results in an approximate twofold increase in ICAM-1 expression as determined by flow cytometry analysis. Pretreatment of epithelial cells with a protein kinase C-α (PKC-α) inhibitor, Gö-6976, also inhibited subsequent lymphocyte adhesion to HDE-exposed epithelial cells. These data suggest that airway epithelial cell HDE exposure enhances subsequent lymphocyte adhesion to epithelial cells that is mediated in part by HDE modulation of ICAM-1 expression and PKC-α.

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Influenza Virus Receptor Specificity and Cell Tropism in Mouse and Human Airway Epithelial Cells

Journal of Virology ◽

10.1128/jvi.02677-05 ◽

2006 ◽

Vol 80 (15) ◽

pp. 7469-7480 ◽

Cited By ~ 239

Author(s):

Aida Ibricevic ◽

Andrew Pekosz ◽

Michael J. Walter ◽

Celeste Newby ◽

John T. Battaile ◽

...

Keyword(s):

Influenza Virus ◽

Epithelial Cell ◽

Epithelial Cells ◽

Airway Epithelial Cell ◽

Airway Epithelial Cells ◽

Influenza Viruses ◽

Mouse Lung ◽

Airway Epithelial ◽

Human Airway ◽

Human Airway Epithelial Cells

ABSTRACT Recent human infections caused by the highly pathogenic avian influenza virus H5N1 strains emphasize an urgent need for assessment of factors that allow viral transmission, replication, and intra-airway spread. Important determinants for virus infection are epithelial cell receptors identified as glycans terminated by an α2,3-linked sialic acid (SA) that preferentially bind avian strains and glycans terminated by an α2,6-linked SA that bind human strains. The mouse is often used as a model for study of influenza viruses, including recent avian strains; however, the selectivity for infection of specific respiratory cell populations is not well described, and any relationship between receptors in the mouse and human lungs is incompletely understood. Here, using in vitro human and mouse airway epithelial cell models and in vivo mouse infection, we found that the α2,3-linked SA receptor was expressed in ciliated airway and type II alveolar epithelial cells and was targeted for cell-specific infection in both species. The α2,6-linked SA receptor was not expressed in the mouse, a factor that may contribute to the inability of some human strains to efficiently infect the mouse lung. In human airway epithelial cells, α2,6-linked SA was expressed and functional in both ciliated and goblet cells, providing expanded cellular tropism. Differences in receptor and cell-specific expression in these species suggest that differentiated human airway epithelial cell cultures may be superior for evaluation of some human strains, while the mouse can provide a model for studying avian strains that preferentially bind only the α2,3-linked SA receptor.

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PM10-stimulated airway epithelial cells activate primary human dendritic cells independent of uric acid: Application of anin vitromodel system exposing dendritic cells to airway epithelial cell-conditioned media

Respirology ◽

10.1111/resp.12316 ◽

2014 ◽

Vol 19 (6) ◽

pp. 881-890 ◽

Cited By ~ 8

Author(s):

Jeremy A. Hirota ◽

Neil E. Alexis ◽

Mandy Pui ◽

SzeWing Wong ◽

Elkie Fung ◽

...

Keyword(s):

Dendritic Cells ◽

Uric Acid ◽

Epithelial Cell ◽

Epithelial Cells ◽

Airway Epithelial Cell ◽

Airway Epithelial Cells ◽

Conditioned Media ◽

Airway Epithelial ◽

Human Dendritic Cells

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Mucin Expression in Airway Epithelial Cells from Children with Bronchiolitis, Healthy Children and RSV Infected Airway Epithelial Cell Cultures.

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a6311 ◽

2009 ◽

Author(s):

AM Fonceca ◽

BF Flanagan ◽

GC Jeffers ◽

RL Smyth ◽

PS McNamara

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Cell Cultures ◽

Airway Epithelial Cell ◽

Airway Epithelial Cells ◽

Healthy Children ◽

Airway Epithelial ◽

Epithelial Cell Cultures ◽

Mucin Expression

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Effective-Component Compatibility of Bufei Yishen Formula Ⅲ Ameliorated COPD By Improving Airway Epithelial Cell Senescence Via Promoting Mitophagy By Nrf2/PINK1 Pathway

10.21203/rs.3.rs-1198975/v1 ◽

2022 ◽

Author(s):

Min-yan Li ◽

Yan-qin Qin ◽

Jian-sheng Li ◽

Peng Zhao ◽

Yan-ge Tian ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cell ◽

Epithelial Cells ◽

Airway Epithelial Cell ◽

Airway Epithelial Cells ◽

Cell Senescence ◽

Chronic Obstructive ◽

Airway Epithelial ◽

Positive Effects ◽

Effective Component

Abstract Background: Effective-component compatibility of Bufei Yishen formula Ⅲ (ECC-BYF Ⅲ) shows positive effects on stable chronic obstructive pulmonary disease (COPD).Purpose: To investigate the mechanisms of ECC-BYF Ⅲ on COPD rats from the aspect of airway epithelial cell senescence.Methods: COPD model rats were treated with ECC-BYF Ⅲ for 8 weeks and the efficacy was evaluated. Cigarette smoke extract (CSE) induced senescence model of airway epithelial cells were treated with ECC-BYF Ⅲ, the related enzymes and proteins involved in oxidative stress and mitophagy were detected.Results: ECC-BYF Ⅲ markedly rescued pulmonary function and histopathological changes, which might be associated with the amelioration of lung senescence, including reduction of malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-9, increase of the level of total superoxide dismutase (T-SOD), and decease of p21 level in airway. Furthermore, ECC-BYF Ⅲ suppressed p16, p21 expressions and senescence-associated β-galactosidase (SA-β-Gal) in CSE-induced airway epithelial cells. Moreover, ECC-BYF Ⅲ upregulated the mitophagy-related proteins, including co-localization of TOM20 and LC3B, PINK1, PARK2, and improved mitochondrial function with upregulating mitochondrial mitofusin (Mfn)2 and reducing dynamin-related protein 1 (Drp1) expression. ECC-BYF Ⅲ enhanced the activities of T-SOD and GSH-PX by up-regulating Nrf2, thus inhibiting oxidative stress. After intervention with Nrf2 inhibitor, the regulation effects of ECC-BYF Ⅲ on oxidative stress, mitophagy and senescence in airway epithelial cells were significantly suppressed.Conclusions: ECC-BYF Ⅲ exerts beneficial effects on COPD rats by ameliorating airway epithelial cell senescence, which is mediated by inhibiting oxidative stress and subsequently enhancing mitophagy through activation of Nrf2 signaling.

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Acrolein stimulates eicosanoid release from bovine airway epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1990.259.4.l222 ◽

1990 ◽

Vol 259 (4) ◽

pp. L222-L229 ◽

Cited By ~ 2

Author(s):

C. A. Doupnik ◽

G. D. Leikauf

Keyword(s):

Arachidonic Acid ◽

Epithelial Cell ◽

Epithelial Cells ◽

Cell Injury ◽

Airway Epithelial Cell ◽

Bronchial Hyperresponsiveness ◽

Airway Epithelial Cells ◽

Arachidonic Acid Metabolism ◽

Airway Epithelial ◽

Lactate Dehydrogenase Activity

Injury to the airway mucosa after exposure to environmental irritants is associated with pulmonary inflammation and bronchial hyperresponsiveness. To better understand the relationships between mediator release and airway epithelial cell injury during irritant exposures, we studied the effects of acrolein, a low-molecular-weight aldehyde found in cigarette smoke, on arachidonic acid metabolism in cultured bovine tracheal epithelial cells. Confluent airway epithelial cell monolayers, prelabeled with “3H”arachidonic acid, released significant levels of 3H activity when exposed (20 min) to 100 microM acrolein. [3H]arachidonic acid products were resolved using reverse-phase high-performance liquid chromatography. Under control conditions the released 3H activity coeluted predominantly with the cyclooxygenase product, prostaglandin (PG) E2. After exposure to acrolein, significant “peaks” in 3H activity coeluted with the lipoxygenase products 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE, as well as with PGE2, PGF2 alpha, and 6-keto-PGF1 alpha. Dose-response relationships for acrolein-induced release of immunoreactive PGF2 alpha and PGE2 from unlabeled epithelial monolayers demonstrated 30 microM acrolein as the threshold dose, with 100 microM acrolein inducing nearly a fivefold increase in both PGF2 alpha and PGE2. Cellular viability after exposure to 100 microM acrolein, determined by released lactate dehydrogenase activity, was not affected until exposure periods were greater than or equal to 2 h. These results implicate the airway epithelial cell as a possible source of eicosanoids after exposure to acrolein.

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