# Mast Cell Chymase and Human Lung Fibroblast Interaction: Mechanisms and Implications for Asthma

## TL;DR

This study explores how mast cell chymase affects human lung fibroblasts, revealing new mechanisms that may contribute to asthma development.

## Contribution

The study identifies novel intracellular effects of chymase on fibroblast signaling and metabolism, independent of PAR activation.

## Key findings

- Chymase degrades fibronectin and alters signaling factors like integrin αVb3, FAK, Src, and Akt in lung fibroblasts.
- Chymase reduces fibroblast motility and suppresses CREB and c-Jun levels or phosphorylation.
- Chymase enters fibroblasts, degrades HSP27, and suppresses metabolic activity without inducing cell death.

## Abstract

Mast cells play a crucial role in the pathogenesis of asthma, by releasing inflammatory mediators including mast cell-specific proteases such as tryptase and chymase. However, the exact role of these proteases in asthma is not fully understood. We showed previously that chymase imposes multiple effects on primary human lung fibroblasts (HLFs), and in the present report we addressed the underlying mechanisms. The effects of chymase on HLFs were found to be independent of protease-activated receptors (PARs), as judged by employing PAR agonists and antagonists, despite PAR1 and PAR3 being highly expressed. Further, Western blot analysis revealed that chymase degraded fibronectin and affected the levels and phosphorylation status of multiple signalling factors related to fibronectin, including integrin αVb3, focal adhesion kinase, Src and Akt. This was associated with a decreased motility of chymase-treated HLFs, as assessed by a cell migration assay. Chymase treatment also suppressed the levels and/or the phosphorylation status of CREB and c-Jun. Intriguingly, chymase was shown to induce the degradation of HSP27, an intracellular protein, suggesting that chymase may exert proteolytic activity in the cell interior. In agreement with this, confocal microscopy analysis revealed that chymase was taken up by the HLFs. By using Seahorse technology, we also demonstrate that chymase has the capacity to suppress the metabolic activity of HLFs, without causing cell death. Altogether, these findings reveal a novel role for mast cell chymase in affecting signalling pathways in HLFs, thereby providing insight into how mast cells potentially can affect the lung microenvironment in asthma.

The online version contains supplementary material available at 10.1007/s10753-026-02460-3.