Soluble PD-L1 improved direct ARDS by reducing monocyte-derived macrophages

Jing Xu,Zhaojun Liu,Qingyuan Zhan,Hongping Qu,Yong Zuo,Wen Yang,Tingting Pan,Xiaoli Wang,Xiaoling Qi,Ruoming Tan,Jiahui Wang,Jialin Liu

doi:10.1038/s41419-020-03139-9

Abstract

Acute respiratory distress syndrome (ARDS) is common in intensive care units (ICUs), although it is associated with high mortality, no effective pharmacological treatments are currently available. Despite being poorly understood, the role of programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) axis in ARDS may provide significant insights into the immunosuppressive mechanisms that occur after ARDS. In the present study, we observed that the level of soluble PD-L1 (sPD-L1), a potential activator of the PD-1 pathway, was upregulated in survivors of direct ARDS than in non-survivors. Administration of sPD-L1 in mice with direct ARDS relieved inflammatory lung injury and improved the survival rate, indicating the protective role of sPD-L1 in direct ARDS. Using high-throughput mass cytometry, we found a marked decrease in the number of lung monocyte-derived macrophages (MDMs) with proinflammatory markers, and the protective role of sPD-L1 diminished in ARDS mice with monocyte/macrophage depletion. Furthermore, PD-1 expression increased in the MDMs of patients and mice with direct ARDS. Finally, we showed that sPD-L1 induced MDM apoptosis in patients with direct ARDS. Taken together, our results demonstrated that the engagement of sPD-L1 on PD-1 expressing macrophages resulted in a decrease in pro-inflammatory macrophages and eventually improved direct ARDS. Our study identified a prognostic indicator for patients with direct ARDS and a potential target for therapeutic development in direct ARDS.

Highlights

Acute respiratory distress syndrome (ARDS) is a common disease in intensive care units (ICUs) caused by various pulmonary or extrapulmonary factors
We found a significant increase in the apoptosis of monocyte-derived macrophages (MDMs) obtained from ARDS patients in soluble PD-L1 (sPD-L1)-treated group compared to IgG/phosphate-buffered saline (PBS)-treated group, whereas the effect didn’t show in those of controls (Fig. 6C, D)
Our study is the first to demonstrate that sPD-L1 was associated with the mortality in patients with direct ARDS and that it played protective roles in the corresponding experimental models

Summary

Introduction

Acute respiratory distress syndrome (ARDS) is a common disease in intensive care units (ICUs) caused by various pulmonary or extrapulmonary factors. The morbidity of ARDS accounts for 10% of ICU admissions and has a high mortality (34.9–46.1%)[1]. Despite this high mortality rate, the pathogenesis of ARDS is not wellunderstood and there were no effective pharmacological treatments. PD-1/PD-L1 axis was demonstrated to mediate the functions of macrophages, thereby participating in some acute inflammatory diseases[4,5,6]. Genome-wide expression measurements revealed that the expression of PD-L1 and PD-L1/PD-1 pathway-associated gene were significantly upregulated in patients with ARDS who survived or were extubated within 28 days compared to non-survivors or intubated patients[7]. Blockade of the PD-1 pathway induced ARDS-like pneumonitis in patients during anti–PD-1/PD-L1 therapy[8,9]

Methods

Results

Conclusion