Abstract
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 SPP1 hi and FABP4 hi 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.
Highlights
Pulmonary fibrosis can occur as a consequence of autoimmunity, environmental exposures, or genetic mutations, as well as idiopathic disease
In order to determine commonalities and differences between Idiopathic pulmonary fibrosis (IPF) and sclerosis-associated interstitial lung disease (SSc-interstitial lung disease (ILD)), we performed single-cell RNA-sequencing on 21 peripheral lung tissue specimens obtained at the time of lung transplant from patients with IPF (n=8 samples) and systemic sclerosis (SSc)-ILD (n=8) and control lung tissue from organ donors without pre-existing lung disease whose lungs were declined for transplant (n=5)
As the progression of disease can be variable in both IPF and SScILD, our analysis focuses on patients with severe disease resulting in respiratory failure by utilizing only explanted tissues from the time of lung transplant
Summary
Pulmonary fibrosis can occur as a consequence of autoimmunity, environmental exposures, or genetic mutations, as well as idiopathic disease. Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) of unknown etiology primarily occurring in the elderly, invariably progressing to respiratory failure, resulting in lung transplant or death. SSc predominantly occurs in women, men with the disease have an increased risk for developing ILD, with an age of presentation between 30-55 years, while IPF predominantly occurs in men, with age of presentation between 60-75 years [5, 6] As it carries the highest rates of disease-associated mortality, primarily driven by pulmonary complications, examining advanced SSc-ILD in comparison to IPF presents a unique window into the role dysregulated immunity may play in pulmonary fibrosis [7, 8]
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