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 13

The high-MIR205HG group exhibits high IL-33 expression and increased number of ILC2s compared with the low-MIR205HG group in patients with IPF.

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The high-MIR205HG group exhibits high IL-33 expression and increased num...
(A) Plot of IL33 expression for healthy lungs (n = 28) and patients with IPF (n = 32) in epithelial cell cluster. (B) Representative images of EpCAM IHC and IL-33 IHC staining in healthy lungs (n = 15) and patients with IPF (n = 29) in the cohort from Supplemental Figure 15A. Scale bar: 100 μm. (C) Plot of EpCAM+ and IL-33+ expression in B. (D) Plot of EpCAM+ and IL-33+ expression in high-MIR205HG group (n = 15) and low-MIR205HG group (n = 14). The 2 groups based on expression of MIR205HG in Figure 1I were used. (E) Plots of EpCAM+ and IL-33+ expression in patients with IPF (n = 29). The median was used as the cutoff value of EpCAM+ and IL-33+ expression. (F) Kaplan-Meier curves for OS rate (%) in patients with IPF (n = 29) divided into high-EpCAM+ and IL-33+ group (n = 15) and low-EpCAM+ and IL-33+ group (n = 14). HR, 4.49; 95% CI, 1.57–12.86; P = 0.0011; P values determined by log-rank test. (G) Representative images of CD127 IHC and GATA3 IHC staining in high-MIR205HG group (n = 15) and low-MIR205HG group (n = 14). Scale bar: 100 μm. (H) Plot of number of ILC2s (CD127+ and GATA3+) in G. *P < 0.05; P values determined by 2-tailed Student’s t test. (I) Correlation analysis of MIR205HG+ and IL33+ epithelial cells using patients with IPF (n = 32). Pearson’s r = 0.799 and P < 0.0001; P values are 2 sided. (J) Plot of IL33+ epithelial cells in high-MIR205HG group (n = 16) and low-MIR205HG group (n = 16). (K) Number of ILC2s (CD127+GATA3+CD45+ cells) in high-MIR205HG group (n = 16) and low-MIR205HG group (n = 16). (L) Schematic illustration of the experimental results. (A, C, D, J, and K) *P < 0.05, ***P < 0.001; P values were determined by 2-tailed Mann-Whitney U test. (J and K) Bars represent the median and 95% CI. (A and I–K) Public scRNA-Seq data (GSE136831) were used for analysis.