Tsoyi, K;
Liang, X;
De Rossi, G;
Ryter, SW;
Xiong, K;
Chu, SG;
Liu, X;
... Rosas, IO; + view all
(2021)
CD148 Deficiency in Fibroblasts Promotes the Development of Pulmonary Fibrosis.
American Journal of Respiratory and Critical Care Medicine
, 204
(3)
pp. 312-325.
10.1164/rccm.202008-3100OC.
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Abstract
RATIONALE: The receptor-like protein tyrosine phosphatase eta (CD148/PTPRJ) exerts anti-fibrotic effects in experimental pulmonary fibrosis via interactions with its ligand syndecan-2; however, the role of CD148 in human pulmonary fibrosis remains incompletely characterized. OBJECTIVES: We investigated the role of CD148 in the profibrotic phenotype of fibroblasts in idiopathic pulmonary fibrosis (IPF). METHODS: Conditional CD148 fibroblast-specific knockout mice were generated and exposed to bleomycin, and then assessed for pulmonary fibrosis. Lung fibroblasts (mouse lung, and human IPF lung), and precision cut lung slices (PCLS) from human IPF patients were isolated and subjected to experimental treatments. A CD148-activating 18-aa mimetic peptide (SDC2-pep) derived from syndecan-2 was evaluated for its therapeutic potential. MEASUREMENTS AND MAIN RESULTS: CD148 expression was downregulated in IPF lungs and fibroblasts. In human IPF lung fibroblasts, silencing of CD148 increased extracellular matrix production and resistance to apoptosis, whereas overexpression of CD148 reversed the profibrotic phenotype. CD148 fibroblast-specific knockout mice displayed increased pulmonary fibrosis after bleomycin challenge compared to control mice. CD148-deficient fibroblasts exhibited hyperactivated PI3K/Akt/mTOR signaling, reduced autophagy and increased p62 accumulation, which induced NF-kB activation and profibrotic gene expression. SDC2-pep reduced pulmonary fibrosis in vivo, and inhibited IPF-derived fibroblast activation. In PCLS from IPF and control patients, SDC2-pep attenuated profibrotic gene expression in IPF and normal lungs stimulated with pro-fibrotic stimuli. CONCLUSIONS: Lung fibroblast CD148 activation reduces p62 accumulation, which exerts anti-fibrotic effects by inhibiting NF-kB mediated profibrotic gene expression. Targeting the CD148 phosphatase with activating ligands such as SDC2-pep may represent a potential therapeutic strategy in IPF.
| Type: | Article |
|---|---|
| Title: | CD148 Deficiency in Fibroblasts Promotes the Development of Pulmonary Fibrosis |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1164/rccm.202008-3100OC |
| Publisher version: | https://doi.org/10.1164/rccm.202008-3100OC |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | CD148, Fibroblast, Idiopathic pulmonary fibrosis, Nuclear Factor-kappa-B, Syndecan-2 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10125961 |
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