# Interleukin-17A Orchestrates Lung Injury and Remodeling Through p53 and uPA System Crosstalk

## TL;DR

This study shows how interleukin-17A contributes to lung injury and fibrosis by interacting with p53 and uPA systems, and suggests that blocking IL-17A could help treat lung damage.

## Contribution

The study reveals a novel mechanistic link between IL-17A, p53, and uPA systems in lung injury and fibrosis, and identifies potential therapeutic targets.

## Key findings

- IL-17A increases p53 and PAI-1 while decreasing uPA and uPAR in alveolar epithelial cells, promoting apoptosis and lung injury.
- Blocking IL-17A with CSP7 or antibodies reduces lung inflammation, fibrosis markers, and collagen content in mice with bleomycin-induced injury.
- IL-17A also enhances profibrogenic markers in lung fibroblasts, suggesting a role in myofibroblast differentiation.

## Abstract

Alveolar inflammation, elevated interleukin-17A (IL-17A), and fibrin deposition are common features in all forms of lung injury followed by fibrotic repair. Type II alveolar epithelial cell (AEC) viability, regulated by tumor suppressor protein p53 and changes in uPA-mediated fibrinolysis, has been linked to lung injury and pulmonary fibrosis (PF). Nevertheless, mechanistic details linking increased IL-17A with p53 and PAI-1 to lung injury and remodeling remain unclear. We found that IL-17A and its receptor (IL-17RA) are induced during various lung injuries. IL-17A augments IL-17RA, p53 and downstream PAI-1 with a concurrent decrease in uPA and its receptor (uPAR) in AECs. These changes promote AEC apoptosis, alveolar injury and PF. In addition, IL-17A causes a dose-dependent increase in IL-17RA and profibrogenic markers in lung fibroblasts (LFs), suggesting myofibroblast differentiation. We further found that inhibition of IL-17A by caveolin-1 scaffolding domain peptide (CSP) or its 7-mer deletion fragment (CSP7) inhibits AEC apoptosis, lung inflammation, and profibrogenic markers in LFs and PF. Further, treatment of mice with bleomycin-induced lung injury using CSP7, an anti-IL-17A antibody, or an IL-17RA blocking antibody attenuates total lung hydroxyproline and soluble collagen content, as well as levels of profibrogenic markers. These observations support the role of IL-17A/IL-17RA signaling in lung injury and post-injury remodeling.