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Research ArticleInflammationPulmonology
Open Access | 
10.1172/jci.insight.187172
1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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1Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.
2Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
3Department of Regulatory Bioorganic Chemistry, SANKEN (the Institute of Scientific and Industrial Research), Osaka, Japan.
4Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
5Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
6Department of Life Science, Graduate School of Advanced Engineering, Chiba Institute of Technology, Chiba, Japan.
7Laboratory of Human Immunology (Single Cell Genomics), WPI Immunology Frontier Research Center, and
8Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka, Japan.
9AIST-Waseda University Computational Bio Big-Data Open Innovation Laboratory (CBBD-OIL), National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
Address correspondence to: Eiichi Morii, Department of Pathology, Osaka University Graduate School of Medicine. 2-2 Yamada-Oka, Suita, Osaka 565-0871, Japan. Phone: 81.6.6879.3871; Email: morii@molpath.med.osaka-u.ac.jp.
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Published March 10, 2025 - More info
Published in Volume 10, Issue 5 on March 10, 2025
AbstractIdiopathic pulmonary fibrosis (IPF) causes remodeling of the distal lung. Pulmonary remodeling is histologically characterized by fibrosis, as well as appearance of basal cells; however, the involvement of basal cells in IPF remains unclear. Here, we focus on the long noncoding RNA MIR205HG, which is highly expressed in basal cells, using RNA sequencing. Through RNA sequencing of genetic manipulations using primary cells and organoids, we discovered that MIR205HG regulates IL-33 expression. Mechanistically, the AluJb element of MIR205HG plays a key role in IL-33 expression. Additionally, we identified a small molecule that targets the AluJb element, leading to decreased IL-33 expression. IL-33 is known to induce type 2 innate lymphoid cells (ILC2s), and we observed that MIR205HG expression was positively correlated with the number of ILC2s in patients with IPF. Collectively, these findings provide insights into the mechanisms by which basal cells contribute to IPF and suggest potential therapeutic targets.
Graphical Abstract
Introduction
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that causes remodeling and fibrosis of the distal lung, ultimately leading to respiratory failure and death (1, 2). The pathogenesis of IPF has not been fully elucidated, but repeated inflammation is thought to cause epithelial cell damage and dysfunction, which lead to fibroblast activation, deposition of extracellular matrix, and subsequent tissue fibrosis (3). Nintedanib and pirfenidone, currently the only US Food and Drug Administration–approved drugs, do not completely halt disease progression (4, 5). Therefore, it is crucial to understand the pathogenesis of IPF and uncover molecular mechanisms to improve the prognosis of IPF.
The distal region of normal lungs is histologically composed of 2 types of epithelial cells: alveolar type I (AT1) cells, which are responsible for gas exchange, and alveolar type II (AT2) cells, which produce surfactant and act as tissue stem cells. However, the distal region of the IPF exhibits histologically characteristic findings termed “honeycombed” cysts, where AT1 and AT2 cells are reduced and replaced by aberrant AT2-like cells and airway epithelial cells, such as basal cells, goblet cells, and ciliated cells (2, 6). This pulmonary remodeling has also been robustly demonstrated in comprehensive single-cell RNA-sequencing (scRNA-Seq) analyses (7–9). Additionally, transcriptomic analysis of bronchoalveolar lavage fluid from patients with IPF has shown that a basal cell signature is associated with enhanced disease progression and mortality (10). However, until recently, it remained uncertain whether this pulmonary remodeling directly contributed to the pathogenesis of IPF or was simply a bystander phenomenon or end-stage finding. Recent studies have revealed that IPF-derived basal cells induced fibroblast proliferation and extracellular matrix deposition both in vitro and in vivo (11, 12). These reports suggest that basal cells directly contribute to the fibrosis of IPF, but insight into the contributions of basal cells to the pathogenesis of IPF remains limited.
lncRNAs, defined as noncoding RNA transcripts longer than 200 nucleotides, are involved in various regulatory steps of gene expression, such as chromatin remodeling, transcription, RNA stability, and translation (13–15). These transcripts are shown to be involved in the biological processes of diseases, including pulmonary fibrosis (15, 16). For example, the lncRNA DNM3OS has been identified as a critical downstream effector of TGF-β–induced myofibroblast activation, regulating the lung fibrotic process by producing pro-fibrotic mature miRNAs (17). Furthermore, the lncRNA FENDRR can reduce lung fibroblast activation by decreasing cellular iron concentration via interactions with IRP1 and acting as a pro-fibrotic miR-214 (18). However, most of these findings have focused on fibroblasts and myofibroblasts; little is known regarding the function of lncRNA expressed in basal cells involved in the pathogenesis of IPF. Therefore, we focused on lncRNA to gain insights concerning the involvement of basal cells in the pathogenesis of IPF.
In this work, we first analyzed public scRNA-Seq data from patients with IPF and identified lncRNA MIR205HG, which is highly expressed in basal cells. MIR205HG was revealed as a prognostic factor in patients with IPF. Through comprehensive analysis of genetic manipulations using primary cells, alveolar epithelial organoids, and airway organoids from IPF patient samples (IPF patient–derived airway organoids), we found that MIR205HG is involved in the regulation of IL-33 expression, which is thought to contribute to the pathogenesis of IPF. Intriguingly, the interaction between the AluJb element of MIR205HG and the Alu element of IL33 was important for these regulatory mechanisms. Additionally, we identified DQzG, a small molecule that reduced IL-33 expression, likely by inhibiting the interaction between Alu elements. Furthermore, MIR205HG expression was positively correlated with IL-33 expression and the number of type 2 innate lymphoid cells (ILC2s) in tissue samples from patients with IPF. These data highlight the involvement of lncRNA MIR205HG in the pathogenesis of IPF and provide important insights into a therapeutic target.
ResultslncRNA MIR205HG is highly expressed in basal cells and an independent poor prognostic factor in IPF. We examined the differences in histological features in alveolar regions between healthy lungs and IPF patient samples. In healthy lungs, alveoli beneath the pleura were lined with AT1 and AT2 cells, whereas in patients with IPF, these alveoli were lined with basophilic bronchial cells due to metaplasia (Figure 1A). The lining cells of normal lungs were positive for SFTPC, whereas those of patients with IPF were positive for KRT5 (Figure 1A). We analyzed public scRNA-Seq data from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) (GSE136831) (7), which included samples from healthy lungs (n = 28) and patients with IPF (n = 32) (Figure 1B and Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.187172DS1), and found that the number of alveolar epithelial cells (including AT2 cells) decreased whereas the number of airway epithelial cells (including basal cells) increased in IPF (Figure 1C). These findings, including the histological features, were consistent with the previous report (7).
Figure 1lncRNA MIR205HG is upregulated in basal cells. (A) Representative images of HE, SFTPC IHC, and KRT5 IHC staining in alveoli beneath the pleura of healthy and IPF lungs. Scale bar: 100 μm. HE, hematoxylin and eosin; SFTPC, surfactant protein C; KRT5, keratin 5. (B) Uniform manifold approximation and projection (UMAP) visualization of cell types in healthy and IPF lungs. (C) Proportion of epithelial cell type distribution in healthy and IPF lungs. (D) Volcano plot and bar graph (basal cell enriched lncRNA) of DEGs in AT2 cells and basal cells. The cutoff values were log2FC > 1, FDR < 0.05. (E) UMAP visualization of MIR205HG expression. (F) Expression of MIR205HG in healthy control and IPF patients. Public bulk RNA-Seq datasets (GSE92592, ref. 19, and GSE124685, ref. 20) were used. Data represent mean ± SD. **P < 0.01, ***P < 0.001; P values were determined by 2-tailed Mann-Whitney U test. (B–E) Public scRNA-Seq data (GSE136831) (7) were used for analysis.
Next, we searched for lncRNAs preferentially expressed in basal cells by comparing AT2 cells and basal cells in public scRNA-Seq data, identifying MIR205HG as the most significant differentially expressed gene (DEG) in basal cells (Figure 1D). Among the lncRNAs expressed in basal cells, MIR205HG was localized to the epithelial cluster and was particularly highly expressed in basal cells (Figure 1E and Supplemental Figure 1B). We sorted AT2 cells and basal cells from metaplastic lesions of 2 IPF cases and performed RNA-Seq, which verified that MIR205HG was among the DEGs preferentially expressed in basal cells (Supplemental Figure 2, A–G). Bulk RNA-Seq data also showed significantly higher expression of MIR205HG in patients with IPF than in healthy controls (GSE92592, ref. 19, and GSE124685, ref. 20) (Figure 1F). These findings indicate that MIR205HG is highly expressed in basal cells within metaplastic lesions.
To assess the clinical implications of MIR205HG in IPF, we conducted in situ hybridization (ISH) on 29 samples from patients with IPF (Figure 2A). The expression level of MIR205HG was scored using HALO software (Figure 2B), and patients were divided into a high-MIR205HG group (n = 15) and a low-MIR205HG group (n = 14) based on the median value (Figure 2C). Kaplan-Meier analysis revealed that the high-MIR205HG group had a significantly lower overall survival (OS) rate than the low-MIR205HG group (HR, 5.23; 95% CI, 1.80–15.17; P = 0.0042) (Figure 2D). Univariate and multivariate Cox regression analyses further demonstrated that MIR205HG was an independent risk factor affecting the OS of patients with IPF (Figure 2E). To reconfirm the significance of MIR205HG in the prognosis of IPF, we compared the expression of MIR205HG between 2 groups of IPF patients: the favorable-prognosis group (n = 16) (survival ≥ 3 years) and the unfavorable-prognosis group (n = 19) (survival < 3 years, n = 13, and lung transplant recipients, n = 6). The expression level of MIR205HG was significantly higher in the unfavorable- than favorable-prognosis group (Figure 2F).
Figure 2lncRNA MIR205HG is an independent poor prognostic factor in patients with IPF. (A) Overview of clinical implication assessment based on MIR205HG expression in patients with IPF (n = 29). UIP, usual interstitial pneumonia. (B) Representative images of MIR205HG ISH staining in patients with IPF. Scale bar: 10 mm. Zoomed image and virtual composite image after HALO software analysis are shown. Scale bar: 50 μm. (C) Plots of MIR205HG expression in patients with IPF (n = 29). The median was used as a cutoff value. (D) Kaplan-Meier curves for OS rate (%) in patients with IPF (n = 29) divided into high-MIR205HG group (n = 15) and low-MIR205HG group (n = 14). HR, 5.23; 95% CI, 1.80–15.17; P = 0.0042. P values were determined by log-rank test. (E) Forest plots of univariate and multivariate Cox regression analysis in the correlation between MIR205HG expression and other clinical factors. P values were determined by Cox proportional hazards method. (F) Representative of whole image of HE and MIR205HG ISH staining. Bar graph of MIR205HG expression in patients with IPF of the favorable-prognosis group (survival ≥ 3 years, n = 16) and the unfavorable-prognosis group (survival < 3 years, n = 13, and lung transplant recipients [LTx recipients], n = 6). Scale bar: 10 mm. Data represent mean ± SD. **P < 0.01; P values were determined by 2-tailed Mann-Whitney U test.
The MIR205HG+IL33+ cell subset in the alveolar region increases in IPF. To clarify the detailed spatial expression of
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