Dysregulated Cell–Cell Communication Characterizes Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a progressive disease of older adults characterized by fibrotic replacement of functional gas exchange units in the lung. The strongest risk factor for IPF is a genetic variantin the promoter region of the gel-forming mucin, <i>MUC5B</i>. To better...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-10-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/11/20/3319 |
| _version_ | 1797474327755489280 |
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| author | Jonathan S. Kurche Ian T. Stancil Jacob E. Michalski Ivana V. Yang David A. Schwartz |
| author_facet | Jonathan S. Kurche Ian T. Stancil Jacob E. Michalski Ivana V. Yang David A. Schwartz |
| author_sort | Jonathan S. Kurche |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) is a progressive disease of older adults characterized by fibrotic replacement of functional gas exchange units in the lung. The strongest risk factor for IPF is a genetic variantin the promoter region of the gel-forming mucin, <i>MUC5B</i>. To better understand how the <i>MUC5B</i> variant influences development of fibrosis, we used the NicheNet R package and leveraged publicly available single-cell RNA sequencing data to identify and evaluate how epithelia participating in gas exchange are influenced by ligands expressed in control, <i>MUC5B</i> variant, and fibrotic environments. We observed that loss of type-I alveolar epithelia (AECI) characterizes the single-cell RNA transcriptome in fibrotic lung and validated the pattern of AECI loss using single nuclear RNA sequencing. Examining AECI transcriptomes, we found enrichment of transcriptional signatures for IL6 and AREG, which we have previously shown to mediate aberrant epithelial fluidization in IPF and murine bleomycin models. Moreover, we found that the protease ADAM17, which is upstream of IL6 trans-signaling, was enriched in control <i>MUC5B</i> variant donors. We used immunofluorescence to validate a role for enhanced expression of ADAM17 among <i>MUC5B</i> variants, suggesting involvement in IPF pathogenesis and maintenance. |
| first_indexed | 2024-03-09T20:28:29Z |
| format | Article |
| id | doaj.art-c3ec233daabe4d669eb83a41eaac1275 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T20:28:29Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-c3ec233daabe4d669eb83a41eaac12752023-11-23T23:29:07ZengMDPI AGCells2073-44092022-10-011120331910.3390/cells11203319Dysregulated Cell–Cell Communication Characterizes Pulmonary FibrosisJonathan S. Kurche0Ian T. Stancil1Jacob E. Michalski2Ivana V. Yang3David A. Schwartz4Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USAProgram in Cellular Biology and Biophysics, Graduate School, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USASchool of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USADepartment of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USAIdiopathic pulmonary fibrosis (IPF) is a progressive disease of older adults characterized by fibrotic replacement of functional gas exchange units in the lung. The strongest risk factor for IPF is a genetic variantin the promoter region of the gel-forming mucin, <i>MUC5B</i>. To better understand how the <i>MUC5B</i> variant influences development of fibrosis, we used the NicheNet R package and leveraged publicly available single-cell RNA sequencing data to identify and evaluate how epithelia participating in gas exchange are influenced by ligands expressed in control, <i>MUC5B</i> variant, and fibrotic environments. We observed that loss of type-I alveolar epithelia (AECI) characterizes the single-cell RNA transcriptome in fibrotic lung and validated the pattern of AECI loss using single nuclear RNA sequencing. Examining AECI transcriptomes, we found enrichment of transcriptional signatures for IL6 and AREG, which we have previously shown to mediate aberrant epithelial fluidization in IPF and murine bleomycin models. Moreover, we found that the protease ADAM17, which is upstream of IL6 trans-signaling, was enriched in control <i>MUC5B</i> variant donors. We used immunofluorescence to validate a role for enhanced expression of ADAM17 among <i>MUC5B</i> variants, suggesting involvement in IPF pathogenesis and maintenance.https://www.mdpi.com/2073-4409/11/20/3319mucin<i>MUC5B</i>rs35705950type-I alveolar epithelial cellfibroblastalveolar macrophage |
| spellingShingle | Jonathan S. Kurche Ian T. Stancil Jacob E. Michalski Ivana V. Yang David A. Schwartz Dysregulated Cell–Cell Communication Characterizes Pulmonary Fibrosis Cells mucin <i>MUC5B</i> rs35705950 type-I alveolar epithelial cell fibroblast alveolar macrophage |
| title | Dysregulated Cell–Cell Communication Characterizes Pulmonary Fibrosis |
| title_full | Dysregulated Cell–Cell Communication Characterizes Pulmonary Fibrosis |
| title_fullStr | Dysregulated Cell–Cell Communication Characterizes Pulmonary Fibrosis |
| title_full_unstemmed | Dysregulated Cell–Cell Communication Characterizes Pulmonary Fibrosis |
| title_short | Dysregulated Cell–Cell Communication Characterizes Pulmonary Fibrosis |
| title_sort | dysregulated cell cell communication characterizes pulmonary fibrosis |
| topic | mucin <i>MUC5B</i> rs35705950 type-I alveolar epithelial cell fibroblast alveolar macrophage |
| url | https://www.mdpi.com/2073-4409/11/20/3319 |
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