MARCH8 downregulation modulates profibrotic responses including myofibroblast differentiation

Area of Science:

• Pulmonary Medicine
• Cell Biology
• Molecular Biology

Background:

• Interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF), have poor patient outcomes due to limited treatment options.
• Understanding the pathological mechanisms driving fibrosis is crucial for developing new therapies.
• The role of Membrane-associated RING-CH 8 (MARCH8) in pulmonary fibrosis and fibroblast activation is largely unknown.

Purpose of the Study:

• To investigate the role of MARCH8 in the pathogenesis of pulmonary fibrosis.
• To determine the effect of transforming growth factor-beta (TGF-β) on MARCH8 expression and function in human lung fibroblasts (HLFs).
• To explore MARCH8 as a potential therapeutic target for IPF.

Main Methods:

• Compared MARCH8 expression in IPF patients and controls, and in bleomycin-induced pulmonary fibrosis models.
• Treated normal and IPF HLFs with TGF-β to assess changes in MARCH8 and fibroblast to myofibroblast transition (FMT) markers (α-SMA, collagen type I, fibronectin).
• Utilized MARCH8 overexpression and siRNA knockdown in HLFs to evaluate its regulatory effects on TGF-β-induced FMT and Smad2/3 phosphorylation.

Main Results:

• MARCH8 expression was significantly decreased in IPF lungs and bleomycin-induced fibrosis models.
• TGF-β reduced MARCH8 expression in HLFs in a dose- and time-dependent manner, correlating with increased FMT markers.
• MARCH8 overexpression suppressed TGF-β-induced FMT, while MARCH8 knockdown enhanced basal and TGF-β-induced FMT marker expression.
• TGF-β-induced decrease in MARCH8 occurred at the transcriptional level and was associated with reduced Smad2/3 phosphorylation.

Conclusions:

• MARCH8 acts as a negative regulator of fibroblast to myofibroblast transition (FMT).
• Downregulation of MARCH8 is implicated in the profibrotic responses observed in IPF.
• MARCH8 represents a novel therapeutic target for treating pulmonary fibrosis.