Involvement of lncRNA MIR205HG in idiopathic pulmonary fibrosis and IL-33 regulation via Alu elements
Tsuyoshi Takashima, Chao Zeng, Eitaro Murakami, Naoko Fujiwara, Masaharu Kohara, Hideki Nagata, Zhaozu Feng, Ayako Sugai, Yasue Harada, Rika Ichijo, Daisuke Okuzaki, Satoshi Nojima, Takahiro Matsui, Yasushi Shintani, Gota Kawai, Michiaki Hamada, Tetsuro Hirose, Kazuhiko Nakatani, Eiichi Morii
Tsuyoshi Takashima, Chao Zeng, Eitaro Murakami, Naoko Fujiwara, Masaharu Kohara, Hideki Nagata, Zhaozu Feng, Ayako Sugai, Yasue Harada, Rika Ichijo, Daisuke Okuzaki, Satoshi Nojima, Takahiro Matsui, Yasushi Shintani, Gota Kawai, Michiaki Hamada, Tetsuro Hirose, Kazuhiko Nakatani, Eiichi Morii
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Research Article Inflammation Pulmonology

Involvement of lncRNA MIR205HG in idiopathic pulmonary fibrosis and IL-33 regulation via Alu elements

Abstract

Idiopathic 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.

Authors

Tsuyoshi Takashima, Chao Zeng, Eitaro Murakami, Naoko Fujiwara, Masaharu Kohara, Hideki Nagata, Zhaozu Feng, Ayako Sugai, Yasue Harada, Rika Ichijo, Daisuke Okuzaki, Satoshi Nojima, Takahiro Matsui, Yasushi Shintani, Gota Kawai, Michiaki Hamada, Tetsuro Hirose, Kazuhiko Nakatani, Eiichi Morii

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Figure 4

A subset of MIR205HG+ abnormal AT2 cells express IL-33 and exist in close proximity to ILC2s in patients with IPF.

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A subset of MIR205HG+ abnormal AT2 cells express IL-33 and exist in clos...
(A) GO analysis of biological processes upregulated in MIR205HG+SFTPC+KRT5– epithelial cells compared with MIR205HG–SFTPC+KRT5– epithelial cells. Pie chart showing 39 processes with significant differences. The parentheses indicate the number of enrichment terms that belong to the process. Significant differences were determined using an enrichment score > 0.7, P < 0.005. Bar graph showing 6 inflammation-related processes among 39 processes. (B) Cell–cell communication network showing the ratio of receptor–ligand pairs between the MIR205HG+SFTPC+KRT5– cells (MIR205HG+ AT2 cells) and other meta cell types, classified as lymphoid, myeloid, stromal, and endothelial cell clusters (Figure 1B) compared with MIR205HG–SFTPC+KRT5– cells (MIR205HG– AT2 cells). P values were determined by the permutation test. (C) Volcano plot of DEGs in MIR205HG–SFTPC+KRT5– cells and MIR205HG+SFTPC+KRT5– cells. The cutoff values were log2FC > 1, FDR < 0.05. (D) Representative confocal images of MIR205HG ISH, HTII-280 IHC, and IL-33 IHC staining in control (n = 3) and IPF patients (n = 3). Orange arrows indicate MIR205HG+HTII-280+IL-33+ AT2 cells. Scale bar: 50 μm. (E) Quantification of AT2 cells expressing MIR205HG and IL-33 in healthy and IPF patients in D. (F) Number of CD127+GATA3+CD45+ cells in healthy (n = 28) and IPF (n = 32) lungs. Bars represent the median and 95% CI. **P < 0.01; P values were determined by 2-tailed Mann-Whitney U test. (G) Representative images of MIR205HG ISH, CD127 IHC, and GATA3 IHC staining in control (n = 4) and IPF patients (n = 4). Scale bar: 50 μm. (A, B, E, and F) Public scRNA-Seq data (GSE136831) were used for analysis.