Discoidin domain receptor 2 signaling through PIK3C2α in fibroblasts promotes lung fibrosis

Area of Science:

• Cell Biology
• Molecular Biology
• Pathology

Background:

• Idiopathic pulmonary fibrosis (IPF) presents a significant health challenge with limited treatment options.
• Type I collagen signaling via discoidin domain receptor 2 (DDR2) is crucial for fibroblast regulation in fibrosis.
• Downstream signaling pathways of DDR2 are not well-defined and represent potential therapeutic targets.

Purpose of the Study:

• To investigate the role of PIK3C2α as a downstream mediator of collagen I/DDR2 signaling in fibroblast activity and progressive fibrosis.
• To determine if the collagen/DDR2/PIK3C2α pathway is a viable target for antifibrotic therapies.

Main Methods:

• Formation of DDR2/PIK3C2α complexes and PIK3C2α phosphorylation were assessed in murine and IPF-derived fibroblasts stimulated with collagen I.
• Fibroblast activation and apoptosis were evaluated following PIK3C2α inhibition or deletion.
• Pulmonary fibrosis was induced by bleomycin treatment in mice with fibroblast-specific PIK3C2α deletion.

Main Results:

• Collagen I stimulation induced DDR2/PIK3C2α complex formation and PIK3C2α phosphorylation in fibroblasts.
• PIK3C2α inhibition or deletion reduced fibroblast activation and increased apoptosis.
• Fibroblast-specific deletion of PIK3C2α attenuated bleomycin-induced pulmonary fibrosis in mice.

Conclusions:

• The collagen/DDR2/PIK3C2α signaling axis is essential for fibroblast function in progressive fibrosis.
• This pathway represents a promising therapeutic target for developing novel antifibrotic treatments for IPF and other fibrotic diseases.