PD-L1 promotes GSDMD-mediated NET release by maintaining the transcriptional activity of Stat3 in sepsis-associated encephalopathy

Abstract

Sepsis-associated encephalopathy (SAE), as shown as acute and long-term cognitive impairment, is associated with increased mortality of sepsis. The causative factors of SAE are diverse and the underlying pathological mechanisms of SAE remain to be fully elucidated. Multiple studies have demonstrated a crucial role of microglia in the development of SAE, but the role of neutrophils and neutrophil extracellular traps (NETs) in SAE is still unclear. Here, we firstly show that in murine sepsis model, neutrophils and NETs promote blood-brain barrier (BBB) disruption, neuronal apoptosis and microglia activation in hippocampus and induce hippocampus-dependent memory impairment. Anti-Gr-1 antibody or DNase I treatment attenuates these sepsis-induced changes. Then, we find that genetic deletion of neutrophil GSDMD or PD-L1 reduces NET release and improves SAE in murine sepsis model. Finally, in human septic neutrophils, p-Y705-Stat3 binds to PD-L1, promotes PD-L1 nuclear translocation and enhances transcription of the gasdermin D (GSDMD) gene. In summary, our findings firstly identify a novel function of PD-L1 in maintaining transcriptional activity of p-Y705-Stat3 to promote GSDMD-dependent NET release in septic neutrophils, which plays a critical role in the development of SAE.

The gasdermin family: emerging therapeutic targets in diseases

“… 288 In human septic neutrophils, GSDMD transcription is regulated by STAT3, which involves nuclear PD-L1 translocation. 289 STAT3 also regulates the transcription of GSDMC, a process that necessitates the participation of nuclear PD-L1. Upon macrophage-derived TNF-α activation, caspase-8 cleaves GSDMC at the D365 site, generating GSDMC-NT, which ultimately leads to pyroptosis.…”

“… 52 In addition, our team demonstrated the deleterious role of GSDMD-mediated NET release in sepsis-associated encephalopathy (SAE), and neutrophil-specific GSDMD knockout reduced plasma and hippocampal NET levels as well as ameliorated inflammatory injury in a murine model of SAE. 289 Neutrophil PD-L1 can be translocated to the nucleus, aided by the help of p-Y705-STAT3, to constitute the nPD-L1/p-Y705-STAT3 complex, which promotes the transcription of GSDMD. Consequently, they and we propose that therapeutically targeting GSDMD to directly inhibit NETosis, or targeting upstream regulators of GSDMD to indirectly inhibit NETosis, may represent an efficacious strategy for the treatment of sepsis.…”

The implication of targeting PD-1:PD-L1 pathway in treating sepsis through immunostimulatory and anti-inflammatory pathways

“…While enhanced PD-L1 expression following surgical brain injury (SBI) can regulate neuroimmune and inflammatory responses through PD-L1 + astrocytes for self-protection and promote nerve repair, the opposite effect occurs in brain injury caused by sepsis ( 148 ). Our previous data showed that during sepsis, PD-L1 binds to P-Y705-Stat3, promoting nuclear translocation of PD-L1 and enhancing the transcription of GSDMD, resulting in increased release of neutrophil extracellular traps (NETs) ( 149 ). Neutrophils and NETs contribute to blood-brain barrier breakdown in the hippocampus, neuronal apoptosis, microglia activation, and hippocampal-dependent memory impairment ( 150 – 153 ).…”

“…Neutrophils and NETs contribute to blood-brain barrier breakdown in the hippocampus, neuronal apoptosis, microglia activation, and hippocampal-dependent memory impairment ( 150 – 153 ). Treatment with anti-Gr-1 antibodies or DNase I has been shown to attenuate these sepsis-induced changes ( 149 ).…”

“…In addition, β-glucan induces an increase in the production of the chemokine CXCL1/2 by PD-L1, which leads to the accumulation of bone marrow neutrophils, weakening the host’s ability to resist fungal infection, and therefore can be used as a potential target for the treatment of fungal sepsis ( 92 ). Treatment with anti-PD-L1 antibodies or DNase I has been shown to attenuate the sepsis-induced changes in the lungs and brains caused by neutrophils ( 136 , 149 , 185 ).…”