# Transient receptor potential vanilloid four in macrophages mediates TGF-β activation to drive myofibroblast differentiation and pulmonary fibrosis

## TL;DR

This study shows that TRPV4 in macrophages helps activate TGF-β, leading to myofibroblast differentiation and lung fibrosis.

## Contribution

The study identifies a novel TRPV4-TGF-β axis in macrophages that drives pulmonary fibrosis.

## Key findings

- Loss of TRPV4 in myeloid cells protects against experimental pulmonary fibrosis.
- TRPV4 in macrophages activates TGF-β in response to matrix stiffness.
- TRPV4-dependent TGF-β activation induces myofibroblast differentiation in fibroblasts.

## Abstract

Emerging evidence suggests that macrophage-fibroblast interactions can drive organ fibrosis. Myofibroblast differentiation is a key step in the pathogenesis of pulmonary fibrosis that requires both a soluble (e.g., TGF-β) and mechanical signal. We have previously implicated the fibroblast mechanosensitive cation channel, transient receptor potential vanilloid 4 (TRPV4), as a mediator of myofibroblast differentiation and experimental pulmonary fibrogenesis in response to matrix biophysical signals. Less is understood regarding how or if the matrix drives macrophage activation to mediate fibrosis. We demonstrate that loss of TRPV4 specifically in myeloid cells protects against experimental pulmonary fibrosis in vivo. Mechanistically, macrophage TRPV4 responds to matrix substrate stiffness in the pathophysiologic range, thereby optimizing TGF-β activation. Macrophage conditioned media transfer and coculture systems demonstrate a profound effect of TRPV4-dependent TGF-β activation in inducing myofibroblast differentiation in fibroblasts. This TGF-β activating effect was dependent on the actinomyosin binding domain within the C-terminal intracytoplasmic tail of TRPV4 and on assembly of actinomyosin cytoskeleton and its force generation. Our current study identifies a novel TRPV4-TGF-β axis in macrophages that drives myofibroblast differentiation and experimental pulmonary fibrosis through optimal activation of TGF-β. As TGF-β is a critical pro-fibrotic factor, these findings are broadly applicable to many fibrotic diseases.