Mir-155-5p targets TP53INP1 to promote proliferative phenotype in hypersensitivity pneumonitis lung fibroblasts

Area of Science:

• Pulmonary Medicine
• Molecular Biology
• Bioinformatics

Background:

• Hypersensitivity pneumonitis (HP) is an inflammatory lung disease that can progress to fibrosis (fHP).
• The molecular mechanisms underlying HP pathogenesis, particularly the role of microRNAs in lung fibroblasts, are not well understood.

Purpose of the Study:

• To identify differentially expressed genes (DEGs) and microRNAs (DE-miRNAs) associated with HP lungs.
• To investigate the role of miR-155-5p in the phenotype of fibrotic HP lung fibroblasts.

Main Methods:

• Integrated bulk RNA-Seq and bioinformatic analyses to identify DEGs and DE-miRNAs.
• In vitro studies using lung fibroblasts to assess miR-155-5p expression and function.
• Loss-of-function and gain-of-function assays to determine miR-155-5p's impact on fibroblast proliferation and senescence.

Main Results:

• A unique transcriptional signature of 53 DEGs was identified in HP lungs, differentiating them from control and idiopathic pulmonary fibrosis (IPF) lungs.
• Eighteen DE-miRNAs were identified, with miR-155-5p implicated in HP pathogenesis.
• Overexpression of miR-155-5p in fHP fibroblasts correlated with reduced TP53INP1 expression, increased proliferation, and decreased senescence, effects mimicked in normal fibroblasts by miR-155-5p overexpression.

Conclusions:

• A distinct set of DEGs and DE-miRNAs, including miR-155-5p, may help differentiate HP from other fibrotic lung diseases.
• miR-155-5p upregulation and subsequent TP53INP1 downregulation in fHP fibroblasts likely contribute to their proliferative and profibrotic phenotype.
• These findings offer insights into the pathogenic mechanisms of HP and potential therapeutic targets.