Anti-PD-L1 antibody alleviates pulmonary fibrosis by inducing autophagy via inhibition of the PI3K/Akt/mTOR pathway

Lu, Ye; Zhong, Wen-Fang; Liu, Yuanyuan; Chen, Weimou; zhang, Jinming; Zeng, Zhao Chong; Huang, Huilian; Qiao, Yujie; Wan, Xin; Meng, Xiang‐Jin; Cai, Shaoxi; Dong, Hangming

doi:10.1016/j.intimp.2021.108504

Cited by 27 publications

(23 citation statements)

References 40 publications

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“…Besides, they further investigated the protein expression level of PD-L1 in primary mouse lung fibroblasts to confirm PD-L1 upregulation at the cellular level. As expected, the primary mouse lung fibroblasts expressed a higher level of PD-L1 (29). Consistent results were also reported in other studies (17,20).…”

Section: Pd-1/pd-l1 Axis and Ipf In Animal Modelssupporting

confidence: 92%

“…Emerging evidence has identified that PD-L1 is also expressed on fibroblasts/myofibroblasts (17, 20, 21, 29) and mesenchymal stem cells (MSCs) (22) in the lung from IPF patients or murine models. In a bleomycin-induced mouse pulmonary fibrosis model, Lu and colleagues observed that the expression level of PD-L1 is significantly upregulated in the lung tissue (29). Besides, they further investigated the protein expression level of PD-L1 in primary mouse lung fibroblasts to confirm PD-L1 upregulation at the cellular level.…”

Section: Pd-1/pd-l1 Axis and Ipf In Animal Modelsmentioning

confidence: 99%

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The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

et al. 2022

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Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with a bleak prognosis. Mounting evidence suggests that IPF shares bio-molecular similarities with lung cancer. Given the deep understanding of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in cancer immunity and the successful application of immune checkpoint inhibitors (ICIs) in lung cancer, recent studies have noticed the role of the PD-1/PD-L1 axis in IPF. However, the conclusions are ambiguous, and the latent mechanisms remain unclear. In this review, we will summarize the role of the PD-1/PD-L1 axis in IPF based on current murine models and clinical studies. We found that the PD-1/PD-L1 pathway plays a more predominant profibrotic role than its immunomodulatory role in IPF by interacting with multiple cell types and pathways. Most preclinical studies also indicated that blockade of the PD-1/PD-L1 pathway could attenuate the severity of pulmonary fibrosis in mice models. This review will bring significant insights into understanding the role of the PD-1/PD-L1 pathway in IPF and identifying new therapeutic targets.

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Section: Pd-1/pd-l1 Axis and Ipf In Animal Modelssupporting

confidence: 92%

Section: Pd-1/pd-l1 Axis and Ipf In Animal Modelsmentioning

confidence: 99%

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

et al. 2022

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“…Recent studies have shown that downregulation of p-mTOR and upregulation of LC3-II protein level, contributing to suppression of collagen deposition and EMT in primary lung fibroblasts and TGF-β1-induced lung epithelial cells, resulting in an alleviation of lung injury and improving lung function in BLM-induced animal models ( Alsayed et al, 2022 ; Pei et al, 2022 ). Accumulating evidence has also shown that the repression of TGF-β1-induced activation of mTOR signaling in lung fibroblasts, which results in the induction of autophagy and the inhibition of myofibroblast activation and ECM production in mice model of BLM-induced pulmonary fibrosis ( Li et al, 2021 ; Lu et al, 2022 ). Furthermore, THSG has been demonstrated to trigger autophagy in human hepatocytes via the inhibition of the PI3K/Akt/mTOR signaling pathway ( Yang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside ameliorates bleomycin-induced pulmonary fibrosis via regulating pro-fibrotic signaling pathways

Huang

Chen

et al. 2022

Front. Pharmacol.

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2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-Glucoside (THSG) is the main active ingredient extracted from Polygonum multiflorum Thunb. (PMT), which has been reported to possess extensive pharmacological properties. Nevertheless, the exact role of THSG in pulmonary fibrosis has not been demonstrated yet. The main purpose of this study was to investigate the protective effect of THSG against bleomycin (BLM)-induced lung fibrosis in a murine model, and explore the underlying mechanisms of THSG in transforming growth factor-beta 1 (TGF-β1)-induced fibrogenesis using MRC-5 human lung fibroblast cells. We found that THSG significantly attenuated lung injury by reducing fibrosis and extracellular matrix deposition. THSG treatment significantly downregulated the expression levels of TGF-β1, fibronectin, α-SMA, CTGF, and TGFBR2, however, upregulated the expression levels of antioxidants (SOD-1 and catalase) and LC3B in the lungs of BLM-treated mice. THSG treatment decreased the expression levels of fibronectin, α-SMA, and CTGF in TGF-β1-stimulated MRC-5 cells. Conversely, THSG increased the expression levels of SOD-1 and catalase. Furthermore, treatment of THSG profoundly reduced the TGF-β1-induced generation of reactive oxygen species (ROS). In addition, THSG restored TGF-β1-induced impaired autophagy, accompany by increasing the protein levels of LC3B-II and Beclin 1. Mechanism study indicated that THSG significantly reduced TGF-β1-induced increase of TGFBR2 expression and phosphorylation of Smad2/3, Akt, mTOR, and ERK1/2 in MRC-5 cells. These findings suggest that THSG may be considered as an anti-fibrotic drug for the treatment of pulmonary fibrosis.

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“…Previous studies have also confirmed the inhibitory effect of AKT/mTOR signaling inactivation on fibroblast migration; notably, applying Morin (an anti-arthritis compound) has been shown to reduce the migration of fibroblasts in rheumatoid arthritis ( 56 ) and Danlou tablet (a Chinese medicine used to treat cardiovascular diseases) has been reported to restrain the migration of vascular adventitial fibroblasts in atherosclerosis ( 57 ). Furthermore, Lu et al revealed that an antibody against programmed cell death ligand 1 could inhibit fibroblast proliferation, migration and ECM deposition in pulmonary fibrosis through regulating the AKT/mTOR signaling pathway ( 58 ). In combination with the changes in the AKT/mTOR signaling pathway detected following laminin α1 knockdown, it may be hypothesized that laminin α1 could regulate the proliferation, apoptosis and migration of fibroblasts, partially via regulating the AKT/mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Laminin α1 as a target for the treatment of epidural fibrosis by regulating fibrotic mechanisms

et al. 2022

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Excessive proliferation and migration of fibroblasts in the lumbar laminectomy area can lead to epidural fibrosis, eventually resulting in failed back surgery syndrome. It has been reported that laminin α1, a significant biofunctional glycoprotein in the extracellular matrix, is involved in several fibrosis-related diseases, such as pulmonary, liver and keloid fibrosis. However, the underlying mechanism of laminin α1 in epidural fibrosis remains unknown. The present study aimed to explore the effect and mechanism of laminin α1 in fibroblast proliferation, apoptosis and migration, and epidural fibrosis. Following the establishment of a laminectomy model, hematoxylin and eosin, Masson's trichrome and immunohistochemical staining were performed to determine the degree of epidural fibrosis, the number of fibroblasts, collagen content and the epidural expression levels of laminin α1, respectively. Furthermore, a stable small interfering RNA system was used to knock down the expression of laminin α1 in fibroblasts. The transfection efficiency was confirmed by reverse transcription-quantitative PCR and immunofluorescence staining. Western blot analysis, scratch wound assay, EdU incorporation assay, flow cytometric analysis and Cell Counting Kit 8 assay were performed to assess the proliferation, apoptosis, migration and viability of fibroblasts, as well as the expression levels of the AKT/mechanistic target of rapamycin (mTOR) signaling-related proteins. In vivo experiments revealed that laminin α1 was positively and time-dependently associated with epidural fibrosis. In addition, laminin α1 knockdown attenuated cell proliferation, viability and migration, and promoted apoptosis. Furthermore, the results revealed that the activation of the AKT/mTOR signaling pathway was involved in the aforementioned processes. Overall, the current study illustrated the positive association between laminin α1 and epidural fibrosis, and also verified the effect of laminin α1 on fibroblast proliferation, apoptosis and migration. Furthermore, the results suggested that the AKT/mTOR signaling pathway may serve a significant role in regulating the behavior of laminin α1-induced fibroblasts.

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Anti-PD-L1 antibody alleviates pulmonary fibrosis by inducing autophagy via inhibition of the PI3K/Akt/mTOR pathway

Cited by 27 publications

References 40 publications

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside ameliorates bleomycin-induced pulmonary fibrosis via regulating pro-fibrotic signaling pathways

Laminin α1 as a target for the treatment of epidural fibrosis by regulating fibrotic mechanisms

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