Antifibrotic Drug Nintedanib Inhibits CSF1R to Promote IL-4-associated Tissue Repair Macrophages

Area of Science:

• Immunology
• Pharmacology
• Cell Biology

Background:

• Macrophage phenotypes in fibrosis are poorly understood, hindering drug development for fibrotic diseases.
• Reprogramming macrophages is a promising therapeutic strategy for managing fibrotic conditions.

Purpose of the Study:

• To identify profibrotic and prohomeostatic macrophage phenotypes.
• To guide the development of macrophage-targeting therapies for fibrotic disease.

Main Methods:

• Utilized nintedanib, a kinase inhibitor, in bleomycin-induced lung fibrosis models.
• Combined in vivo and in vitro bulk and single-cell RNA-sequencing.
• Investigated effects on mouse and human primary macrophages.

Main Results:

• Nintedanib upregulated IL-4/IL-13 pathway genes in lung macrophages in vivo and in vitro.
• This effect was linked to colony stimulating factor 1 (CSF1) receptor inhibition.
• Nintedanib promoted tissue repair gene expression by counterbalancing TNF effects.

Conclusions:

• Nintedanib enhances IL-4 signaling in macrophages via CSF1 receptor inhibition.
• This mechanism promotes tissue repair phenotypes, contributing to nintedanib's antifibrotic effects.
• Findings clarify macrophage roles in fibrosis and therapeutic targeting.