Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis.

Area of Science:

• Pulmonary Medicine
• Immunology
• Fibrotic Diseases

Background:

• Previous studies suggest limiting complement activation can suppress TGF-β signaling.
• The precise hierarchical interactions between TGF-β and complement in lung fibrosis remain unclear.

Purpose of the Study:

• To investigate the mechanisms by which TGF-β induces complement activation in lung fibrosis pathogenesis.
• To elucidate the role of complement receptors C3a and C5a in TGF-β-mediated lung fibrosis.

Main Methods:

• Adenoviral vectors overexpressing TGF-β were administered to C57-BL6 mice.
• RNA interference (RNAi) targeting C3a or C5a receptors (C3ar or C5ar) was used to silence these pathways.
• Histopathological analysis, collagen content measurement, and miRNA profiling were performed.

Main Results:

• Genetic silencing of C3ar or C5ar arrested TGF-β-induced lung fibrosis, collagen deposition, and local complement activation.
• Silencing C3ar or C5ar led to Smad7 recovery (a TGF-β inhibitor) and diminished local release of decay-accelerating factor (DAF).
• TGF-β-mediated loss of DAF was prevented by receptor blockade in human lung epithelial cells; C3a also caused DAF loss.

Conclusions:

• TGF-β activates complement, promoting lung fibrosis through C3a and C5a signaling pathways.
• Targeting complement receptors C3ar and C5ar offers a potential therapeutic strategy for lung fibrosis.
• TGF-β and complement interactions influence miRNA regulation involved in epithelial cell fate and fibrosis.