Interleukin-17A Orchestrates Lung Injury and Remodeling Through p53 and uPA System Crosstalk
Durgesh Nandini Das, Akarsha Balnadupete, Rashmi Shetty, Venkadesa Perumal Gopu, Rushil Sajjan, Yashodhar P. Bhandary, Amarnath S. Marudamuthu, Christian Oliver, Aarav Patel, Aryan Patel, Buka Samten, Yoichiro Iwakura, Hua Tang, Deborah E. Citrin, Jay Peters, Sreerama Shetty
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.
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…
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Taxonomy
TopicsInterstitial Lung Diseases and Idiopathic Pulmonary Fibrosis · Caveolin-1 and cellular processes · Psoriasis: Treatment and Pathogenesis