PD-L1 maintains neutrophil extracellular traps release by inhibiting neutrophil autophagy in endotoxin-induced lung injury

• Published in: Frontiers in immunology 2022-08, Vol.13, p.949217
• Main Authors: Zhu, Cheng-Long, Xie, Jian, Zhao, Zhen-Zhen, Li, Peng, Liu, Qiang, Guo, Yu, Meng, Yan, Wan, Xiao-Jian, Bian, Jin-Jun, Deng, Xiao-Ming, Wang, Jia-Feng
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - pathology; anti-PD-L1 therapy; ARDS; Autophagy; B7-H1 Antigen - metabolism; Endotoxins - adverse effects; Extracellular Traps - metabolism; Humans; Immunology; Lipopolysaccharides - adverse effects; neutrophil extracellular traps; Neutrophils; PD-L1; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Respiratory Distress Syndrome - chemically induced; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.949217

Programmed death ligand 1 (PD-L1) is not only an important molecule in mediating tumor immune escape, but also regulates inflammation development. Here we showed that PD-L1 was upregulated on neutrophils in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Neutrophil specific knockout of PD-L1 reduced lung injury in ARDS model induced by intratracheal LPS injection. The level of NET release was reduced and autophagy is elevated by PD-L1 knockout in ARDS neutrophils both and . Inhibition of autophagy could reverse the inhibitory effect of PD-L1 knockout on NET release. PD-L1 interacted with p85 subunit of PI3K at the endoplasmic reticulum (ER) in neutrophils from ARDS patients, activating the PI3K/Akt/mTOR pathway. An extrinsic neutralizing antibody against PD-L1 showed a protective effect against ARDS. Together, PD-L1 maintains the release of NETs by regulating autophagy through the PI3K/Akt/mTOR pathway in ARDS. Anti-PD-L1 therapy may be a promising measure in treating ARDS.