Programmed death ligand-1 (PD-L1) levels were significantly higher in lungs of patients with idiopathic pulmonary fibrosis (IPF) and might mediate fibroblast to myofibroblast transition (FMT) through 2 different pathways, according to a new study published in Scientific Reports.

The team of researchers led by Guo observed an overall upregulation of PD-L1 in lungs of both humans and mice with pulmonary fibrosis and further tested this protein’s effects on molecular levels in mice. When performing a PD-L1 knockdown transforming growth factor β (TGF-β), the activity of ɑ smooth muscle actin (ɑ-SMA) and β-catenin diminished. PD-L1 was further proved to be required for TGF-β induced FMT in both healthy and ill lungs.

Likewise, TGF-β seems to upregulate PD-L1 in a dependent mechanism on Smad3 and p38. TGF-β is known to play a key role in FMT by promoting the interaction between PD-L1 and Smad3. Asides from the Smad3 pathway, the glycogen synthase kinase 3 β (GSKβ)/β-catenin signaling also seemed to mediate FMT in a dependent manner of PD-L1, and the inhibition of β-catenin also reduced TGF-β induced FMT.


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“Smad3 and p38 activation result in upregulation of PD-L1 in [human lung fibroblasts]. The increased PD-L1 binds to Smad3 and further facilitates its transcriptional activity in the nucleus. On the other hand, PD-L1 also enhances TGF-β-induced phosphorylation of GSK3β at Serine 9, thereby inhibiting the degradation of β-catenin mediated by GSK3β, resulting in upregulation of β-catenin,” the authors said.

“Accumulated β-catenin then translocates into the nucleus where it binds and promotes the transcriptional factor T cell factor activity, contributing to FMT target gene expression. α-SMA is shown as one of the target genes that are unregulated by Smad3 and the β-catenin pathway.”

In the context of a challenging disease in terms of diagnosis, treatment, and prognosis, the full understanding of IPF physiopathology becomes important. Although many advances have been made, the specific mechanisms that drive IPF molecular level remain unclear. Despite that more studies are yet to be done, the revealing role of PD-L1 highlighted in this publication suggests a possible therapeutic target for patients with IPF.

Reference

Guo X, Sunil C, Adeyanju O et al. PD-L1 mediates lung fibroblast to myofibroblast transition through Smad3 and β-catenin signaling pathways. Sci Rep. Published online February 23, 2022. doi:10.1038/s41598-022-07044-3