Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease
Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced...
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| Format: | Article |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.595811/full |
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| author | Eleanor Valenzi Tracy Tabib Anna Papazoglou John Sembrat Humberto E. Trejo Bittar Mauricio Rojas Robert Lafyatis |
| author_facet | Eleanor Valenzi Tracy Tabib Anna Papazoglou John Sembrat Humberto E. Trejo Bittar Mauricio Rojas Robert Lafyatis |
| author_sort | Eleanor Valenzi |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced SSc-ILD to IPF provides insight to the role dysregulated immunity may play in pulmonary fibrosis. To analyze cell-type specific transcriptome commonalities and differences between IPF and SSc-ILD, we compared single-cell RNA-sequencing (scRNA-seq) of 21 explanted lung tissue specimens from patients with advanced IPF, SSc-ILD, and organ donor controls. Comparison of IPF and SSc-ILD tissue identified divergent patterns of interferon signaling, with interferon-gamma signaling upregulated in the SPP1hi and FABP4hi macrophages, cytotoxic T cells, and natural kill cells of IPF, while type I interferon signaling and production was upregulated in the corresponding SSc-ILD populations. Plasmacytoid dendritic cells were found in diseased lungs only, and exhibited upregulated cellular stress pathways in SSc-ILD compared to IPF. Alveolar type I cells were dramatically decreased in both IPF and SSc-ILD, with a distinct transcriptome signature separating these cells by disease. KRT5-/KRT17+ aberrant basaloid cells exhibiting markers of cellular senescence and epithelial-mesenchymal transition were identified in SSc-ILD for the first time. In summary, our study utilizes the enriched capabilities of scRNA-seq to identify key divergent cell types and pathways between IPF and SSc-ILD, providing new insights into the shared and distinct mechanisms between idiopathic and autoimmune interstitial lung diseases. |
| first_indexed | 2024-12-20T04:01:25Z |
| format | Article |
| id | doaj.art-bc785957a44d45c49c778df6c7966fa8 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T04:01:25Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-bc785957a44d45c49c778df6c7966fa82022-12-21T19:54:09ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.595811595811Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung DiseaseEleanor Valenzi0Tracy Tabib1Anna Papazoglou2John Sembrat3Humberto E. Trejo Bittar4Mauricio Rojas5Robert Lafyatis6Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United StatesDivision of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, United StatesDivision of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, United StatesDivision of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Pathology, University of Pittsburgh, Pittsburgh, PA, United StatesDivision of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United StatesDivision of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, United StatesIdiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) differ in the predominant demographics and identified genetic risk alleles of effected patients, however both diseases frequently progress to respiratory failure and death. Contrasting advanced SSc-ILD to IPF provides insight to the role dysregulated immunity may play in pulmonary fibrosis. To analyze cell-type specific transcriptome commonalities and differences between IPF and SSc-ILD, we compared single-cell RNA-sequencing (scRNA-seq) of 21 explanted lung tissue specimens from patients with advanced IPF, SSc-ILD, and organ donor controls. Comparison of IPF and SSc-ILD tissue identified divergent patterns of interferon signaling, with interferon-gamma signaling upregulated in the SPP1hi and FABP4hi macrophages, cytotoxic T cells, and natural kill cells of IPF, while type I interferon signaling and production was upregulated in the corresponding SSc-ILD populations. Plasmacytoid dendritic cells were found in diseased lungs only, and exhibited upregulated cellular stress pathways in SSc-ILD compared to IPF. Alveolar type I cells were dramatically decreased in both IPF and SSc-ILD, with a distinct transcriptome signature separating these cells by disease. KRT5-/KRT17+ aberrant basaloid cells exhibiting markers of cellular senescence and epithelial-mesenchymal transition were identified in SSc-ILD for the first time. In summary, our study utilizes the enriched capabilities of scRNA-seq to identify key divergent cell types and pathways between IPF and SSc-ILD, providing new insights into the shared and distinct mechanisms between idiopathic and autoimmune interstitial lung diseases.https://www.frontiersin.org/articles/10.3389/fimmu.2021.595811/fullsystemic sclerosissystemic sclerosis (scleroderma)idiopathic pulmonary fibrosisinterstitial lung disease (ILD)single-cell RNA-sequencing (scRNA-seq) |
| spellingShingle | Eleanor Valenzi Tracy Tabib Anna Papazoglou John Sembrat Humberto E. Trejo Bittar Mauricio Rojas Robert Lafyatis Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease Frontiers in Immunology systemic sclerosis systemic sclerosis (scleroderma) idiopathic pulmonary fibrosis interstitial lung disease (ILD) single-cell RNA-sequencing (scRNA-seq) |
| title | Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease |
| title_full | Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease |
| title_fullStr | Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease |
| title_full_unstemmed | Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease |
| title_short | Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease |
| title_sort | disparate interferon signaling and shared aberrant basaloid cells in single cell profiling of idiopathic pulmonary fibrosis and systemic sclerosis associated interstitial lung disease |
| topic | systemic sclerosis systemic sclerosis (scleroderma) idiopathic pulmonary fibrosis interstitial lung disease (ILD) single-cell RNA-sequencing (scRNA-seq) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.595811/full |
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