TY - JOUR
T1 - IL-23 amplifies the epithelial-mesenchymal transition of mechanically conditioned alveolar epithelial cells in rheumatoid arthritis-associated interstitial lung disease through mTOR/S6 signaling
AU - Zhang, Chujie
AU - Wang, Shaohua
AU - Lau, Jessica
AU - Roden, Anja C.
AU - Matteson, Eric L.
AU - Sun, Jie
AU - Luo, Fengming
AU - Tschumperlin, Daniel J.
AU - Vassallo, Robert
N1 - Funding Information:
This study was supported by funding from the Hurvis Foundation, the Rheumatology Research Foundation, and Sun Pharma to R.V. C.Z. was supported by the National Natural Science Foundation of China Grant (NSFC, No. 32070764).
Funding Information:
R. Vassallo has received research funding from Pfizer, Bristol Myers Squibb, and Sun Pharma. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.
Publisher Copyright:
Copyright © 2021 the American Physiological Society.
PY - 2021/12
Y1 - 2021/12
N2 - Epithelial-mesenchymal transition (EMT) creates an environment facilitating fibrosis following alveolar epithelial cell injury. IL-23 has important roles in chronic autoimmune conditions like rheumatoid arthritis (RA), but its role in the interstitial lung disease that affects patients with RA is unclear. This study aimed to determine the profibrogenic role of IL-23 on somatic alveolar type I (ATI) epithelial cells. Primary ATI cells were isolated from rats and cultured on plastic dishes for 1–3 wk. After prolonged culture (>14 days) on rigid culture dishes, primary ATI cells gradually acquired a mesenchymal phenotype, identified by decreased expression of caveolin-1, and reorganization of F-actin cytoskeleton, indicating the initiation of EMT by matrix stiffness. To determine how IL-23 promotes EMT in vitro, transitioning ATI cells, cultured on a stiff substrate for >14 days were stimulated with IL-23. The EMT phenotype was significantly enhanced by IL-23, which upregulated a-smooth muscle actin (a-SMA), collagen I/III protein, and decreased caveolin-1. Furthermore, IL-23 significantly promoted cell invasion, as well as apoptotic resistance on transitioning ATI cells. Mechanistically, IL-23-induced EMT was mammalian target of rapamycin/ribosomal protein S6 (mTOR/S6) signaling dependent and reversible by rapamycin. Transcriptional sequencing analysis of human lung fibrosis biopsy tissue revealed key roles for IL-23 in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). This result was further validated by significantly upregulated IL-23 expression at the mRNA level in RA-ILD lung sections. Notably, transitioning ATI epithelial cells were abundantly detected in RA-ILD tissue. Taken together, these data support a role for IL-23 in the pathogenesis of RA lung fibrosis by promoting EMT in alveolar epithelial cells through mTOR/S6 signaling.
AB - Epithelial-mesenchymal transition (EMT) creates an environment facilitating fibrosis following alveolar epithelial cell injury. IL-23 has important roles in chronic autoimmune conditions like rheumatoid arthritis (RA), but its role in the interstitial lung disease that affects patients with RA is unclear. This study aimed to determine the profibrogenic role of IL-23 on somatic alveolar type I (ATI) epithelial cells. Primary ATI cells were isolated from rats and cultured on plastic dishes for 1–3 wk. After prolonged culture (>14 days) on rigid culture dishes, primary ATI cells gradually acquired a mesenchymal phenotype, identified by decreased expression of caveolin-1, and reorganization of F-actin cytoskeleton, indicating the initiation of EMT by matrix stiffness. To determine how IL-23 promotes EMT in vitro, transitioning ATI cells, cultured on a stiff substrate for >14 days were stimulated with IL-23. The EMT phenotype was significantly enhanced by IL-23, which upregulated a-smooth muscle actin (a-SMA), collagen I/III protein, and decreased caveolin-1. Furthermore, IL-23 significantly promoted cell invasion, as well as apoptotic resistance on transitioning ATI cells. Mechanistically, IL-23-induced EMT was mammalian target of rapamycin/ribosomal protein S6 (mTOR/S6) signaling dependent and reversible by rapamycin. Transcriptional sequencing analysis of human lung fibrosis biopsy tissue revealed key roles for IL-23 in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). This result was further validated by significantly upregulated IL-23 expression at the mRNA level in RA-ILD lung sections. Notably, transitioning ATI epithelial cells were abundantly detected in RA-ILD tissue. Taken together, these data support a role for IL-23 in the pathogenesis of RA lung fibrosis by promoting EMT in alveolar epithelial cells through mTOR/S6 signaling.
KW - Alveolar epithelial cells
KW - EMT
KW - IL-23
KW - Pulmonary fibrosis
KW - RA-ILD
UR - http://www.scopus.com/inward/record.url?scp=85120785617&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85120785617&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00292.2021
DO - 10.1152/ajplung.00292.2021
M3 - Article
C2 - 34585990
AN - SCOPUS:85120785617
SN - 1040-0605
VL - 321
SP - L1006-L1022
JO - American Journal of Physiology
JF - American Journal of Physiology
IS - 6
ER -