An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup

Christenson, Stephanie A.; Berge, Maarten van den; Faiz, Alen; Inkamp, Kai; Bhakta, Nirav R.; Bonser, Luke R.; Zlock, Lorna; Barjaktarević, Igor; Barr, R. Graham; Bleecker, Eugene R.; Boucher, Richard C.; Bowler, Russell P.; Comellas, Alejandro P.; Curtis, Jeffrey L.; Han, Mei Lan K.; Hansel, Nadia N.; Hiemstra, Pieter S.; Kaner, Robert J.; Krishnanm, Jerry A.; Martínez, Fernando J.; O’Neal, Wanda K.; Paine, Robert; Timens, Wim; Wells, James M.; Spira, Avrum; Erle, David J.; Woodruff, Prescott G.

doi:10.1172/jci121087

Cited by 84 publications

(85 citation statements)

References 69 publications

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“…MUC1 has been shown to be induced by IFNγ 31 and IFNγ was shown to be protective in a mouse model of pneumococcal pneumonia 32 . Of note, Serum Amyloid A2 (SAA2) is also a part of this network downstream of HNF4A, and was recently described as a COPD-associated IL17 response signature gene in bronchial airway epithelial brushings 33 . We furthermore extended this network with microRNAs that were differentially expressed in CAP or Figure 2.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

Bertrams

Griss

Han

et al. 2020

Sci Rep

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Lower respiratory infections, such as community-acquired pneumonia (cAp), and chronic obstructive pulmonary disease (copD) rank among the most frequent causes of death worldwide. improved diagnostics and profound pathophysiological insights are urgent clinical needs. in our cohort, we analysed transcriptional networks of peripheral blood mononuclear cells (pBMcs) to identify central regulators and potential biomarkers. We investigated the mRnA-and miRnA-transcriptome of pBMcs of healthy subjects and patients suffering from CAP or AECOPD by microarray and Taqman Low Density Array. Genes that correlated with PBMC composition were eliminated, and remaining differentially expressed genes were grouped into modules. One selected module (120 genes) was particularly suitable to discriminate AECOPD and CAP and most notably contained a subset of five biologically relevant mRNAs that differentiated between CAP and AECOPD with an AUC of 86.1%. Likewise, we identified several microRNAs, e.g. miR-545-3p and miR-519c-3p, which separated AECOPD and CAP. We furthermore retrieved an integrated network of differentially regulated mRNAs and microRNAs and identified HNF4A, MCC and MUC1 as central network regulators or most important discriminatory markers. in summary, transcriptional analysis retrieved potential biomarkers and central molecular features of cAp and AecopD. Community acquired pneumonia (CAP) is clinically defined by a sudden onset of severe illness that is accompanied by signs of lower respiratory tract infection, fever, cough and dyspnoea 1. When left untreated, severe secondary effects such as organ damage and occurrence of bacteria in the blood (bacteremia) can ensue. While subject to variance due to region, season and population characteristics, the incidence of CAP is estimated to lie between 1.5 and 14 cases per 1,000 persons per year, with children under 5 years of age and the elderly of more than 65 years being most strongly affected 2. Immunocompromised persons also bear a higher risk of CAP contraction. The leading underlying cause of CAP is infection with the gram-positive bacterium Streptococcus pneumoniae, accounting for 30-35% of CAP cases worldwide 3. The initial colonization of the nasopharynx and the upper respiratory tract often remains asymptomatic. Aspiration into the alveoli can cause severe respiratory or systemic disease, depending on the host immune status and the pneumococcal serotype 1. As CAP is a multifaceted disease with a host of potential causative agents, the robust identification of microR-NAs that are functionally involved in pneumonia depends on the pathogen. In severe Influenza A Virus (H1N1)

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Section: Discussionmentioning

confidence: 99%

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

Bertrams

Griss

Han

et al. 2020

Sci Rep

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“…TNF␣ϩIL-17 induce pendrin-mediated HCO 3 Ϫ secretion. Both TNF␣ and IL-17 have been reported to modify transcriptional activity in epithelia (17,47). To identify HCO 3…”

Section: Tnf␣ϩil-17 Alkalinize Asl Through Cftr and Non-cftrmentioning

confidence: 99%

TNFα and IL-17 alkalinize airway surface liquid through CFTR and pendrin

Rehman

Thornell

Pezzulo

et al. 2020

American Journal of Physiology-Cell Physiology

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The pH of airway surface liquid (ASL) is a key factor that determines respiratory host defense; ASL acidification impairs and alkalinization enhances key defense mechanisms. Under healthy conditions, airway epithelia secrete base (HCO3¯) and acid (H+) to control ASL pH (pHASL). Neutrophil-predominant inflammation is a hallmark of several airway diseases, and TNFα and IL-17 are key drivers. However, how these cytokines perturb pHASL regulation is uncertain. In primary cultures of differentiated human airway epithelia, TNFα decreased and IL-17 did not change pHASL. However, the combination (TNFα+IL-17) markedly increased pHASL by increasing HCO3¯ secretion. TNFα+IL-17 increased expression and function of two apical HCO3¯ transporters, CFTR anion channels and pendrin Cl-/HCO3- exchangers. Both were required for maximal alkalinization. TNFα+IL-17 induced pendrin expression primarily in secretory cells where it was co-expressed with CFTR. Interestingly, significant pendrin expression was not detected in CFTR-rich ionocytes. These results indicate that TNFα+IL-17 stimulate HCO3- secretion via CFTR and pendrin to alkalinize ASL, which may represent an important defense mechanism in inflamed airways.

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“…Type I alpha I collagen (COL1A1), type III alpha I collagen (COL3A1), ELN, MMP9, MMP12, TIMP3, TNF gene expressions were from existing microarray datasets through Gene Expression Omnibus (GEO). The data were analyzed using Bioconductor in R as previously described [13,14].…”

Section: Gene Expression In Human Crc Microarray Datasetmentioning

confidence: 99%

Elastin is a key factor of tumor development in colorectal cancer

Jiang

et al. 2020

BMC Cancer

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Background: Colorectal cancer (CRC) is the most common cancer and a leading cause of death worldwide. Extracellular matrix (ECM) proteins regulate tumor growth and development in CRC. Elastin (ELN) is a component of ECM proteins involved in the tumor microenvironment. However, the role of ELN in CRC remains unclear. Methods: In this study, we analyzed ELN gene expression in tumors from CRC patients and adjacent non-tumor colon tissues and healthy controls from two existing microarray datasets. ELN protein was measured in human normal colon cells and colon cancer epithelial cells and tumor development was assessed in colon epithelial cells cultured in medium with or without ELN peptide on plates coated with ELN recombinant protein. Control plates were coated with PBS only. Results: We found ELN gene expression was increased in tumors from CRC patients compared to adjacent nontumor tissues and healthy controls. ELN protein was increased in cancer cells compared to normal colon epithelial cells. Transforming growth factor beta (TGF-β) was a key cytokine to induce production of ECM proteins, but it did not induce ELN expression in colon cancer cells. Matrix metalloproteinase 9 (MMP9) gene expression was increased, but that of MMP12 (elastase) did not change between CRC patients and control. Tissue inhibitor of metalloproteinases 3 (TIMP3) gene expression was decreased in colon tissues from CRC patients compared to healthy controls. However, MMP9, MMP12 and TIMP3 proteins were increased in colon cancer cells. ELN recombinant protein increased proliferation and wound healing in colon cancer epithelial cells. This had further increased in cancer cells incubated in plates coated with recombinant ELN coated plate and in culture media containing ELN peptide. A potential mechanism was that ELN induced epithelial mesenchymal transition with increased alpha-smooth muscle actin and vimentin proteins but decreased E-cadherin protein. Tumor necrosis factor alpha (TNF) mRNA was also increased in CRC patients compared to controls. ELN recombinant protein induced further increases in TNF protein in mouse bone marrow derived macrophages after lipopolysaccharide stimulation. Conclusions: These data suggest ELN regulates tumor development and the microenvironment in CRC.

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An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup

Cited by 84 publications

References 69 publications

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation

TNFα and IL-17 alkalinize airway surface liquid through CFTR and pendrin

Elastin is a key factor of tumor development in colorectal cancer

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