Epithelial Cells
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Kempaiah Rayavara ◽  
Alexander Kurosky ◽  
Yashoda Madaiah Hosakote

Respiratory syncytial virus (RSV) is an important human pathogen that causes severe lower respiratory tract infections in young children, the elderly, and the immunocompromised, yet no effective treatments or vaccines are available. The precise mechanism underlying RSV-induced acute airway disease and associated sequelae are not fully understood; however, early lung inflammatory and immune events are thought to play a major role in the outcome of the disease. Moreover, oxidative stress responses in the airways plays a key role in the pathogenesis of RSV. Oxidative stress has been shown to elevate cytosolic calcium (Ca2+) levels, which in turn activate Ca2+-dependent enzymes, including transglutaminase 2 (TG2). Transglutaminase 2 is a multifunctional cross-linking enzyme implicated in various physiological and pathological conditions; however, its involvement in respiratory virus-induced airway inflammation is largely unknown. In this study, we demonstrated that RSV-induced oxidative stress promotes enhanced activation and release of TG2 from human lung epithelial cells as a result of its translocation from the cytoplasm and subsequent release into the extracellular space, which was mediated by Toll-like receptor (TLR)-4 and NF-κB pathways. Antioxidant treatment significantly inhibited RSV-induced TG2 extracellular release and activation via blocking viral replication. Also, treatment of RSV-infected lung epithelial cells with TG2 inhibitor significantly reduced RSV-induced matrix metalloprotease activities. These results suggested that RSV-induced oxidative stress activates innate immune receptors in the airways, such as TLRs, that can activate TG2 via the NF-κB pathway to promote cross-linking of extracellular matrix proteins, resulting in enhanced inflammation.

Liubov Bakhchova ◽  
Phatcharida Jantaree ◽  
Anubhuti Gupta ◽  
Berend Isermann ◽  
Ulrike Steinmann ◽  

Alexander M Pallazola ◽  
Jessica X Rao ◽  
Dawit T Mengistu ◽  
Maria S Morcos ◽  
Mariam S Toma ◽  

In chronic obstructive pulmonary disease (COPD), lung natural killer cells (NKs) lyse autologous lung epithelial cells in vitro, but underlying mechanisms and their relationship to epithelial cell apoptosis in vivo are undefined. Although this cytolytic capacity of lung NKs depends on priming by dendritic cells (DC), whether priming correlates with DC maturation or is limited to a specific DC subset are also unknown. We recruited ever-smokers (≥10 pack-years) (n=96) undergoing clinically-indicated lung resections. We analyzed lung NKs for cytotoxic molecule transcripts and for cytotoxicity, which we correlated with in situ detection of activated Caspase-3/7+ airway epithelial cells. To investigate DC priming, we measured lung DC expression of CCR2, CCR7, and CX3CR1, and co-cultured peripheral blood NKs with autologous lung DC, either matured using LPS (non-obstructed smokers) or separated into conventional DC type-1 (cDC1) versus cDC type-2 (cDC2) (COPD). Lung NKs in COPD expressed more perforin (p<0.02) and granzyme B (p<0.03) transcripts; inhibiting perforin blocked in vitro killing by lung NKs. Cytotoxicity in vitro correlated significantly (Sr=0.68, p=0.0043) with numbers of apoptotic epithelial cells per airway. In non-obstructed smokers, LPS-induced maturation enhanced DC-mediated priming of blood NKs, reflected by greater epithelial cell death. Although CCR7 expression was greater in COPD in both cDC1 (p<0.03) and cDC2 (p=0.009), only lung cDC1 primed NK killing. Thus, rather than being intrinsic to those with COPD, NK priming is a capacity of human lung DC that is inducible by recognition of bacterial (and possibly other) danger signals and restricted to the cDC1 subset.

Rahwa Taddese ◽  
Rian Roelofs ◽  
Derk Draper ◽  
Xinqun Wu ◽  
Shaoguang Wu ◽  

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.

2021 ◽  
Vol 8 ◽  
Xiaofang Xu ◽  
Morgan Mann ◽  
Dianhua Qiao ◽  
Yi Li ◽  
Jia Zhou ◽  

Bromodomain-containing protein 4 plays a central role in coordinating the complex epigenetic component of the innate immune response. Previous studies implicated BRD4 as a component of a chromatin-modifying complex that is dynamically recruited to a network of protective cytokines by binding activated transcription factors, polymerases, and histones to trigger their rapid expression via transcriptional elongation. Our previous study extended our understanding of the airway epithelial BRD4 interactome by identifying over 100 functionally important coactivators and transcription factors, whose association is induced by respiratory syncytial virus (RSV) infection. RSV is an etiological agent of recurrent respiratory tract infections associated with exacerbations of chronic obstructive pulmonary disease. Using a highly selective small-molecule BRD4 inhibitor (ZL0454) developed by us, we extend these findings to identify the gene regulatory network dependent on BRD4 bromodomain (BD) interactions. Human small airway epithelial cells were infected in the absence or presence of ZL0454, and gene expression profiling was performed. A highly reproducible dataset was obtained which indicated that BRD4 mediates both activation and repression of RSV-inducible gene regulatory networks controlling cytokine expression, interferon (IFN) production, and extracellular matrix remodeling. Index genes of functionally significant clusters were validated independently. We discover that BRD4 regulates the expression of its own gene during the innate immune response. Interestingly, BRD4 activates the expression of NFκB/RelA, a coactivator that binds to BRD4 in a BD-dependent manner. We extend this finding to show that BRD4 also regulates other components of its functional interactome, including the Mediator (Med) coactivator complex and the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) subunits. To provide further insight into mechanisms for BRD4 in RSV expression, we mapped 7,845 RSV-inducible Tn5 transposase peaks onto the BRD4-dependent gene bodies. These were located in promoters and introns of cytostructural and extracellular matrix (ECM) formation genes. These data indicate that BRD4 mediates the dynamic response of airway epithelial cells to RNA infection by modulating the expression of its coactivators, controlling the expression of host defense mechanisms and remodeling genes through changes in promoter accessibility.

2021 ◽  
Jesse Peterson ◽  
Kinga Balogh Sivars ◽  
Ambra Bianco ◽  
Katja Roeper

Toll-like receptors (TLRs) in mammalian systems are well characterised for their role in innate immunity. In addition, TLRs also fulfil crucial functions outside immunity, including the dorso-ventral patterning function of the original Toll receptor in Drosophila and neurogenesis in mice. Recent discoveries in flies suggested key roles for TLRs in epithelial cells in patterning of cytoskeletal activity near epithelial junctions. Here we address the function of TLRs and the downstream key signal transduction component IRAK4 (interleukin-1 receptor associated kinase 4) in human epithelial cells. Using differentiated human Caco-2 cells as a model for the intestinal epithelium, we show that these cells exhibit baseline TLR signalling as revealed by p-IRAK4 and that blocking IRAK4 function leads to a loss of epithelial tightness involving key changes at tight junctions and adherens junctions. These changes correlate with a loss of epithelial tension and changes in junctional actomyosin. Knock-down of IRAK4 and certain TLRs phenocopies the inhibitor treatment. These data suggest a model whereby TLR receptors near epithelial junctions might be involved in a continuous sensing of the epithelial state to promote epithelial tightness and integrity.

Yueyang Zhong ◽  
Kai Wang ◽  
Yin Zhang ◽  
Qichuan Yin ◽  
Su Li ◽  

Corneal wound involves a series of complex and coordinated physiological processes, leading to persistent epithelial defects and opacification. An obstacle in the treatment of ocular diseases is poor drug delivery and maintenance. In this study, we constructed a Wnt/β-catenin pathway inhibitor, XAV939-loaded liposome (XAV939 NPs), and revealed its anti-inflammatory and antiangiogenic effects. The XAV939 NPs possessed excellent biocompatibility in corneal epithelial cells and mouse corneas. In vitro corneal wound healing assays demonstrated their antiangiogenic effect, and LPS-induced expressions of pro-inflammatory genes of IL-1β, IL-6, and IL-17α were significantly suppressed by XAV939 NPs. In addition, the XAV939 NPs significantly ameliorated alkali-burned corneas with slight corneal opacity, reduced neovascularization, and faster recovery, which were attributed to the decreased gene expressions of angiogenic and inflammatory cytokines. The findings supported the potential of XAV939 NPs in ameliorating corneal wound and suppressing neovascularization, providing evidence for their clinical application in ocular vascular diseases.

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