Jamel El-Benna and Pham My-Chan Dang

Université de Paris, INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex, Faculté de Médecine Xavier Bichat, 75018 Paris, France.

 

Polymorphonuclear neutrophils (PMN) are the most abundant circulating leukocytes. PMN are terminally differentiated cells and have a short life span, but are essential for host defense against microbes. They are the first cells to migrate out of the circulation and to be massively recruited at the infection site where they recognize microbes via different receptors expressed at their cell surface, inducing the engulfment of the microbe into a phagosome and its killing through the release of reactive oxygen species (ROS), myeloperoxidase, glucosidases, proteases and anti-bacterial peptides. Microbes can also be trapped and killed by neutrophil extracellular traps (NETs). PMN can die by apoptosis, NETosis, autophagy, pyroptosis, necroptosis or necrosis. They are then phagocytized and eliminated by local macrophages through a process called efferocytosis, resulting in the cleaning up of the infection site. However, when PMN are excessively activated and have delayed apoptosis, they can become harmful to surrounding tissues through the induction of cell injury and persistent inflammatory reaction, which are driving factors for inflammatory disorders such as rheumatoid arthritis, inflammatory bowel diseases, lung inflammation and sepsis. In tissues PMN have a longer life span than in the blood circulation due to the presence of survival factors such as G-CSF and GM-CSF at the inflammatory site. However, the factors responsible for dysregulation of neutrophil apoptosis in inflammatory conditions are still not completely identified. In the issue of Blood, Wang et al** demonstrate that PD-L1 plays a key role by delaying neutrophil apoptosis at the inflammatory site through the activation of the PI3K-AKT pathway.

Programmed cell death-1 (PD-1) protein, expressed on immune cells, is an immune checkpoint inhibitory receptor that triggers immunosuppressive signaling pathways. PD-1 binds to PD-L1 or PD-L2 and blocks activating signals from T-cell receptors and CD28. PD-1/PD-L1 functions as brakes to limit the adaptive immune response, mainly the beneficial T-cell functions in cancer. PD-L1 is expressed at the plasma membrane of T-lymphocytes, B-lymphocytes and antigen-presenting cells and in some non-lymphoid tissues and non-immune cells. Cancer cells also express PD-L1, which binds to T cell surface via PD-1 allowing them to escape host immune response. Thus, anti-PD-1/anti-PD-L1 antibodies have been used to treat various types of cancer. In this new study, Wang et al**. show that PD-L1 was overexpressed in neutrophils from septic patients and correlates with neutrophil survival. Silencing PD-L1 expression using siRNA accelerated apoptosis of septic neutrophils. Interestingly, neutrophils challenged with IFN-γ+LPS and neutrophils from septic patients exhibited increased AKT phosphorylation, which was reversed by PD-L1 siRNA. They revealed that PD-L1 binds to the p85 subunit of PI3K, the upstream regulator of AKT. In vivo, neutrophil PD-L1 deletion reduced neutrophil lung infiltration in a cecal-ligation and puncture murine model and attenuated lung injury. Thus, increased PD-L1 expression on human neutrophils during inflammation delays cellular apoptosis via PI3K-AKT pathway, driving lung injury and mortality. The study by Wang et al**., brings significant new information to the neutrophil field. The first important message is that PD-L1 is not only a key player in cancer immunomodulation, but also in inflammation, raising the possibility that it could be a novel pharmacological target and that antibodies to PD-L1 could be tested in inflammatory diseases. The second is that PD-L1 up-regulation in neutrophils during inflammation and sepsis promotes their survival. The third is that it highlights the novel and important role of PD-L1 as an inducer of the PI3K-AKT signaling pathway, which regulates many neutrophil inflammatory functions. Thus, this study adds another critical step to our understanding of the neutrophil biology.

 

*Summury of the editorial by: El-Benna J, Dang PM. Live or die: PD-L1 delays neutrophil apoptosis. Blood. 2021 Sep 2;138(9):744-746.

**Wang J, Wang Y, Xie J, Zhao Z et al. Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental animal model of sepsis. Blood. 2021, Sep 2;138(9):806-810.