scholarly journals SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway

2021 ◽  
Author(s):  
Shahanshah Khan ◽  
Mahnoush S. Shafiei ◽  
Christopher Longoria ◽  
John Schoggins ◽  
Rashmin C. Savani ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Lung Epithelial Cells ◽  
Dependent Manner ◽  
S Protein ◽  
Cytokines And Chemokines ◽  
Lung Epithelial ◽  
Mouse Macrophages ◽  
Human And Mouse

Pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1b, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid (N) proteins. When stimulated with extracellular S protein, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-kB pathway in a MyD88-dependent manner. Further, such an activation of the NF-kB pathway is abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induces IL-6, TNF-a, and IL-1b in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.

scholarly journals SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-kB pathway

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shahanshah Khan ◽  
Mahnoush Shafiei ◽  
Christopher Longoria ◽  
John W Schoggins ◽  
Rashmin Savani ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Inflammatory Response ◽  
Inflammatory Cytokines ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Dependent Manner ◽  
S Protein ◽  
Cytokines And Chemokines ◽  
Mouse Macrophages ◽  
Human And Mouse

The pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induced inflammatory cytokines and chemokines including IL-6, IL-1b, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and nucleocapsid (N) proteins. When stimulated with extracellular S protein, human and mouse lung epithelial cells also produced inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly were non-inflammatory, but elicited an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-kB pathway in a MyD88-dependent manner. Further, such an activation of the NF-kB pathway was abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induced IL-6, TNF-a, and IL-1b in wild-type, but not Tlr2-deficient mice. Notably, upon recognition of S protein, TLR2 dimerizes with TLR1 or TLR6 to activate the NF-kB pathway. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.

scholarly journals DRP1-Mediated Mitochondrial Fission Regulates the Lung Epithelial Response to Allergen

2021 ◽  
Author(s):  
Sierra Bruno ◽  
Amit Kumar ◽  
Zoe Mark ◽  
Ravishankar Chandrasekaran ◽  
Emily Nakada ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Mitochondrial Fission ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Airway Epithelial ◽  
Cytokines And Chemokines ◽  
Lung Epithelial ◽  
Pro Inflammatory Cytokines

Abstract Background: Mitochondria regulate a myriad of cellular needs and functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthmatics. Because of their multifaceted nature, mitochondrial structure needs to be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1), a cytosolic GTPase, is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in allergic airway disease. Methods: We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional ablation of DRP1 in lung epithelial cells to investigate mitochondrial fission and its impact on the pro-inflammatory response to House Dust Mite (HDM) in vitro and in vivo. Results: Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of DRP1 in lung epithelial cells lead to decreased mitochondrial fission and enhanced pro-inflammatory signaling in response to HDM. Analysis of lung epithelial specific DRP1 deletion in mice demonstrated enhanced Airway Hyper Responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death. Conclusions: Mitochondrial fission is rapidly upregulated in airway epithelial cells following HDM exposure, prior to epithelial release of pro-inflammatory cytokines and chemokines. Deletion of DRP1, a necessary pro- fission protein, reduces fission and enhances the pro-inflammatory epithelial response to HDM, exacerbating the allergic response.

scholarly journals Cell-surface translocation of annexin A2 contributes to bleomycin-induced pulmonary fibrosis by mediating inflammatory response in mice

2019 ◽  
Vol 133 (7) ◽  
pp. 789-804 ◽  
Author(s):  
Yunlong Lei ◽  
Kui Wang ◽  
Xuefeng Li ◽  
Yi Li ◽  
Xuping Feng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Inflammatory Response ◽  
Cell Surface ◽  
Annexin A2 ◽  
Lung Epithelial Cells ◽  
Cancer Drug ◽  
Autophagic Flux ◽  
Lung Epithelial ◽  
Surface Translocation

Abstract Bleomycin, a widely used anti-cancer drug, may give rise to pulmonary fibrosis, a serious side effect which is associated with significant morbidity and mortality. Despite the intensive efforts, the precise pathogenic mechanisms of pulmonary fibrosis still remain to be clarified. Our previous study showed that bleomycin bound directly to annexin A2 (ANXA2, or p36), leading to development of pulmonary fibrosis by impeding transcription factor EB (TFEB)-induced autophagic flux. Here, we demonstrated that ANXA2 also played a critical role in bleomycin-induced inflammation, which represents another major cause of bleomycin-induced pulmonary fibrosis. We found that bleomycin could induce the cell surface translocation of ANXA2 in lung epithelial cells through exosomal secretion, associated with enhanced interaction between ANXA2 and p11. Knockdown of ANXA2 or blocking membrane ANXA2 mitigated bleomycin-induced activation of nuclear factor (NF)-κB pathway and production of pro-inflammatory cytokine IL-6 in lung epithelial cells. ANXA2-deficient (ANXA2−/−) mice treated with bleomycin exhibit reduced pulmonary fibrosis along with decreased cytokine production compared with bleomycin-challenged wild-type mice. Further, the surface ANXA2 inhibitor TM601 could ameliorate fibrotic and inflammatory response in bleomycin-treated mice. Taken together, our results indicated that, in addition to disturbing autophagic flux, ANXA2 can contribute to bleomycin-induced pulmonary fibrosis by mediating inflammatory response.

scholarly journals Cytotoxic Effects of Air Freshener Biocides in Lung Epithelial Cells

2013 ◽  
Vol 8 (9) ◽  
pp. 1934578X1300800
Author(s):  
Jung-Taek Kwon ◽  
Mimi Lee ◽  
Gun-Baek Seo ◽  
Hyun-Mi Kim ◽  
Ilseob Shim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Epithelial Cells ◽  
Cell Viability ◽  
Lung Epithelial Cells ◽  
Ros Generation ◽  
Dependent Manner ◽  
Cytotoxic Effects ◽  
Lung Epithelial ◽  
Dose Dependent ◽  
A549 Lung

This study evaluated the cytotoxicity of mixtures of citral (CTR) and either benzisothiazolinone (BIT, Mix-CTR-BIT) or triclosan (TCS, Mix-CTR-TCS) in human A549 lung epithelial cells. We investigated the effects of various mix ratios of these common air freshener ingredients on cell viability, cell proliferation, reactive oxygen species (ROS) generation, and DNA damage. Mix-CTR-BIT and Mix-CTR-TCS significantly decreased the viability of lung epithelial cells and inhibited cell growth in a dose-dependent manner. In addition, both mixtures increased ROS generation, compared to that observed in control cells. In particular, cell viability, growth, and morphology were affected upon increase in the proportion of BIT or TCS in the mixture. However, comet analysis showed that treatment of cells with Mix-CTR-BIT or Mix-CTR-TCS did not increase DNA damage. Taken together, these data suggested that increasing the content of biocides in air fresheners might induce cytotoxicity, and that screening these compounds using lung epithelial cells may contribute to hazard assessment.

Titanium dioxide nanoparticles induce an adaptive inflammatory response and invasion and proliferation of lung epithelial cells in chorioallantoic membrane

2015 ◽  
Vol 136 ◽  
pp. 424-434 ◽  
Author(s):  
Estefany I. Medina-Reyes ◽  
Alejandro Déciga-Alcaraz ◽  
Verónica Freyre-Fonseca ◽  
Norma L. Delgado-Buenrostro ◽  
José O. Flores-Flores ◽  
...  
Keyword(s):  
Titanium Dioxide ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Titanium Dioxide Nanoparticles ◽  
Chorioallantoic Membrane ◽  
Lung Epithelial Cells ◽  
Lung Epithelial

Dexamethasone inhibits inflammatory response via down regulation of AP-1 transcription factor in human lung epithelial cells

Gene ◽  
2018 ◽  
Vol 645 ◽  
pp. 85-94 ◽  
Author(s):  
Rajeshwari H. Patil ◽  
M. Naveen Kumar ◽  
K.M. Kiran Kumar ◽  
Rashmi Nagesh ◽  
K. Kavya ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Human Lung ◽  
Lung Epithelial Cells ◽  
Down Regulation ◽  
Lung Epithelial ◽  
Human Lung Epithelial Cells

scholarly journals Inhibition of acute lethal pulmonary inflammation by the IDO–AhR pathway

2017 ◽  
Vol 114 (29) ◽  
pp. E5881-E5890 ◽  
Author(s):  
Soung-Min Lee ◽  
Ha Young Park ◽  
Young-Sill Suh ◽  
Eun Hye Yoon ◽  
Juyang Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Pulmonary Inflammation ◽  
Lung Parenchyma ◽  
Lung Epithelial Cells ◽  
Dependent Manner ◽  
Independent Manner ◽  
Hematopoietic Stem ◽  
Lung Epithelial ◽  
Ifn Γ

The lung is a prototypic organ that was evolved to reduce immunopathology during the immune response to potentially hazardous endogenous and exogenous antigens. In this study, we show that donor CD4+ T cells transiently induced expression of indoleamine 2,3-dioxygenase (IDO) in lung parenchyma in an IFN-γ–dependent manner early after allogeneic hematopoietic stem cell transplantation (HSCT). Abrogation of host IDO expression by deletion of the IDO gene or the IFN-γ gene in donor T cells or by FK506 treatment resulted in acute lethal pulmonary inflammation known as idiopathic pneumonia syndrome (IPS). Interestingly, IL-6 strongly induced IDO expression in an IFN-γ–independent manner when deacetylation of STAT3 was inhibited. Accordingly, a histone deacetylase inhibitor (HDACi) could reduce IPS in the state where IFN-γ expression was suppressed by FK506. Finally, l-kynurenine produced by lung epithelial cells and alveolar macrophages during IPS progression suppresses the inflammatory activities of lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor pathway. Taken together, our results reveal that IDO is a critical regulator of acute pulmonary inflammation and that regulation of IDO expression by HDACi may be a therapeutic approach for IPS after HSCT.

scholarly journals The neuropeptides VIP and PACAP inhibit SARS-CoV-2 replication in monocytes and lung epithelial cells, decrease the production of proinflammatory cytokines, and VIP levels are associated with survival in severe Covid-19 patients

2020 ◽  
Author(s):  
Jairo R. Temerozo ◽  
Carolina Q. Sacramento ◽  
Natalia Fintelman-Rodrigues ◽  
Camila R. R. Pão ◽  
Caroline S. de Freitas ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Clinical Investigation ◽  
Inflammatory Marker ◽  
Scientific Evidence ◽  
Lung Epithelial Cells ◽  
Negative Regulator ◽  
Viral Production ◽  
Inflammatory Reactions ◽  
Cytokines And Chemokines ◽  
Lung Epithelial

AbstractInfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may elicit uncontrolled and damaging inflammatory reactions, due to an excessive immune response and dysregulated production of cytokines and chemokines. Thus, it is critical to identify compounds able to inhibit virus replication and thwart the excessive inflammatory reaction and tissue lesions secondary to SARS-CoV-2 infection. Here, we show that the neuropeptides VIP and PACAP, molecules endowed with immunoregulatory properties, were able to inhibit SARS-CoV-2 RNA synthesis/replication in human monocytes and viral production in lung epithelial cells. VIP and PACAP protected these cells from virus-induced cytopathicity, reduced the production of proinflammmatory mediators, and prevented the SARS-CoV-2-induced NF-kB activation, which is critically involved in the production of inflammatory mediators. Both neuropeptides promoted CREB activation in infected monocytes, a transcription factor with antiapoptotic activity and also a negative regulator of NF-kB. As a possible host response to control patient inflammation, we identified that VIP levels were elevated in plasma from patients with severe forms of COVID-19, correlating with the inflammatory marker CRP and survival on those patients. Since a synthetic form of VIP is clinically approved in Europe and under two clinical trials for patients with COVID-19, our results provide the scientific evidence to further support clinical investigation of these neuropeptides against COVID-19.

Urokinase induces its own expression in Beas2B lung epithelial cells

2002 ◽  
Vol 283 (2) ◽  
pp. L319-L328 ◽  
Author(s):  
Sreerama Shetty ◽  
Usha R. Pendurthi ◽  
Prathap Kumar Shetty Halady ◽  
Ali O. Azghani ◽  
Steven Idell
Keyword(s):  
Epithelial Cells ◽  
Tyrosine Kinase ◽  
Lung Inflammation ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Lung Epithelial Cells ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Amino Terminal ◽  
Lung Epithelial

The urokinase-type plasminogen activator (uPA) interacts with its receptor (uPAR) to promote local proteolysis as well as cellular proliferation and migration. These functions contribute to the pathogenesis of lung inflammation and remodeling as well as the growth and invasiveness of lung neoplasms. In this study, we sought to determine if uPA alters its own expression in lung epithelial cells. Using immunoprecipitation and Western and Northern blotting techniques, we found that uPA treatment enhanced uPA expression in Beas2B lung epithelial cells in a time- and concentration-dependent manner. The induction of uPA expression is mediated through its cell surface receptor uPAR and does not require uPA enzymatic activity. The amino-terminal fragment of uPA, lacking the catalytic domain, is sufficient to induce uPA expression. The serine protease plasmin and the protease inhibitor aprotinin failed to alter uPA-mediated uPA expression, whereas α-thrombin potentiated the response. Pretreatment of Beas2B cells with a tyrosine kinase inhibitor, herbimycin, suggests that activation of tyrosine kinase(s) is involved in the uPA-mediated uPA expression. Induction of uPA expression by exposure of lung-derived epithelial cells to uPA is a newly defined pathway by which this protease could influence expression of local fibrinolytic activity and other uPA-dependent cellular responses germane to lung inflammation or neoplasia.

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