Details

Autor(en) / Beteiligte

• Xiao, Rui
• Gu, Lei
• Li, An-mao
• Gan, Yi-ling
• He, Chun-yan
• Liao, Jia-xin
• Li, Yi-shi
• Xu, Li
• Guo, Shu-liang

Titel

IL-11 drives the phenotypic transformation of tracheal epithelial cells and fibroblasts to enhance abnormal repair after tracheal injury

Ist Teil von

• Biochimica et biophysica acta. Molecular cell research, 2023-04, Vol.1870 (4), p.119438-119438, Article 119438

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2023

Quelle

Elektronische Zeitschriftenbibliothek (Open access)

Beschreibungen/Notizen

• Tracheal stenosis (TS) is a multifactorial and heterogeneous disease that can easily lead to respiratory failure and even death. Interleukin-11 (IL-11) has recently received increased attention as a fibrogenic factor, but its function in TS is uncertain. This study aimed to investigate the role of IL-11 in TS regulation based on clinical samples from patients with TS and a rat model of TS produced by nylon brush scraping. Using lentiviral vectors expressing shRNA (lentivirus-shRNA) targeting the IL-11 receptor (IL-11Rα), we lowered IL-11Rα levels in the rat trachea. Histological and immunostaining methods were used to evaluate the effects of IL-11Rα knockdown on tracheal injury, molecular phenotype, and fibrosis in TS rats. We show that IL-11 was significantly elevated in circulating serum and granulation tissue in patients with TS. In vitro, TGFβ1 dose-dependently stimulated IL-11 secretion from human tracheal epithelial cells (Beas-2b) and primary rat tracheal fibroblasts (PRTF). IL-11 transformed the epithelial cell phenotype to the mesenchymal cell phenotype by activating the β-catenin pathway. Furthermore, IL-11 activated the atypical ERK signaling pathway, stimulated fibroblasts proliferation, and transformed fibroblasts into alpha-smooth muscle actin (α-SMA) positive myofibroblasts. IL-11-neutralizing antibodies (IL-11NAb) or ERK inhibitors (U0126) inhibited IL-11 activity and downregulated fibrotic responses involving TGFβ/SMAD signaling. In vivo, IL-11Rα knockdown rats showed unobstructed tracheal lumen, relatively intact epithelial structure, and significantly reduced granulation tissue proliferation and collagen fiber deposition. Our findings confirm that IL-11 may be a target for future drug prevention and treatment of tracheal stenosis. •IL-11 expression is upregulated in the serum and granulation tissue of patients with TS.•IL-11 participates in the phenotypic transformation of Beas-2b by activating the β-catenin pathway.•IL-11 activates the atypical ERK signaling pathway to induce PRTF proliferation and transformation into myofibroblasts.•IL-11Rα knockdown attenuates TS in rats by inhibiting granulation tissue proliferation and ECM deposition after tracheal injury.