Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis

Wang, Jiafeng; Wang, Yunpeng; Xie, Jian; Zhao, Zhenzhen; Gupta, Sahil; Guo, Yu; Jia, Songhui; Parodo, Jean; Marshall, John C.; Deng, Xiaoming

doi:10.1182/blood.2020009417

Cited by 100 publications

(76 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PD-L1, HLA-DR and CD64 are upregulated in neutrophils exposed to IFN-γ, consistent with our transcriptomic signature data 28–34. The IL-8 receptor CXCR1 was downregulated, potentially reflecting agonist-mediated internalisation of this G protein-coupled receptor.…”

Section: Resultssupporting

confidence: 87%

Ageing and interferon gamma response drive the phenotype of neutrophils in the inflamed joint

et al. 2022

View full text Add to dashboard Cite

ObjectiveNeutrophils are typically the most abundant leucocyte in arthritic synovial fluid. We sought to understand changes that occur in neutrophils as they migrate from blood to joint.MethodsWe performed RNA sequencing of neutrophils from healthy human blood, arthritic blood and arthritic synovial fluid, comparing transcriptional signatures with those from murine K/BxN serum transfer arthritis. We employed mass cytometry to quantify protein expression and sought to reproduce the synovial fluid phenotype ex vivo in cultured healthy blood neutrophils.ResultsBlood neutrophils from healthy donors and patients with active arthritis showed largely similar transcriptional signatures. By contrast, synovial fluid neutrophils exhibited more than 1600 differentially expressed genes. Gene signatures identified a prominent response to interferon gamma (IFN-γ), as well as to tumour necrosis factor, interleukin-6 and hypoxia, in both humans and mice. Mass cytometry confirmed that healthy and arthritic donor blood neutrophils are largely indistinguishable but revealed a range of neutrophil phenotypes in synovial fluid defined by downregulation of CXCR1 and upregulation of FcγRI, HLA-DR, PD-L1, ICAM-1 and CXCR4. Reproduction of key elements of this signature in cultured blood neutrophils required both IFN-γ and prolonged culture.ConclusionsCirculating neutrophils from patients with arthritis resemble those from healthy controls, but joint fluid cells exhibit a network of changes, conserved across species, that implicate IFN-γ response and ageing as complementary drivers of the synovial fluid neutrophil phenotype.

show abstract

Section: Resultssupporting

confidence: 87%

Ageing and interferon gamma response drive the phenotype of neutrophils in the inflamed joint

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Furthermore, as compared with classical neutrophils and PMN-MSDCs, N2 TAN produce higher levels of chemokines but lower granules and ROS [ 75 , 76 ]. PD-L1-expressing neutrophils have been identified in cancer, infections, autoimmunity, and sepsis [ 77 , 78 , 79 , 80 , 81 ] and appear to be less prone to apoptosis than their PDL-1-negative counterparts [ 81 ]. Interestingly, these PDL-1-expressing neutrophils suppress the immune response by limiting activity of PD-1-expressing cells [ 77 , 78 , 79 , 80 , 81 ], culminating in either a protective or deleterious role according to the pathological context.…”

Section: Neutrophils: From Phagocytosis Sentinel To Immunoregulation ...mentioning

confidence: 99%

Specific NLRP3 Inflammasome Assembling and Regulation in Neutrophils: Relevance in Inflammatory and Infectious Diseases

Paget

Doz-Deblauwe

Winter

et al. 2022

Cells

View full text Add to dashboard Cite

The NLRP3 inflammasome is a cytosolic multimeric protein platform that leads to the activation of the protease zymogen, caspase-1 (CASP1). Inflammasome activation mediates the proteolytic activation of pro-inflammatory cytokines (IL-1β and IL-18) and program cell death called pyroptosis. The pyroptosis is mediated by the protein executioner Gasdermin D (GSDMD), which forms pores at the plasma membrane to facilitate IL-1β/IL-18 secretion and causes pyroptosis. The NLRP3 inflammasome is activated in response to a large number of pathogenic and sterile insults. However, an uncontrolled inflammasome activation may drive inflammation-associated diseases. Initially, inflammasome-competent cells were believed to be limited to macrophages, dendritic cells (DC), and monocytes. However, emerging evidence indicates that neutrophils can assemble inflammasomes in response to various stimuli with functional relevance. Interestingly, the regulation of inflammasome in neutrophils appears to be unconventional. This review provides a broad overview of the role and regulation of inflammasomes—and more specifically NLRP3—in neutrophils.

show abstract

“…A study has shown that inhibiting the CDK4/6 pathway can inhibit the NET production pathway and cause apoptosis [ 19 ]. The inhibition of AKT prevented NETs production and instead switched to caspase-dependent apoptotic pathways [ 37 ]. AKT is associated with several proteins related to cell survival, including GSK-3β, P21, and P27 [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

Delayed neutrophil apoptosis may enhance NET formation in ARDS

Chen

Mao

et al. 2022

Respir Res

View full text Add to dashboard Cite

Background Acute respiratory distress syndrome (ARDS) is a neutrophil-associated disease. Delayed neutrophil apoptosis and increased levels of neutrophil extracellular traps (NETs) have been described in ARDS. We aimed to investigate the relationship between these phenomena and their potential as inflammation drivers. We hypothesized that delayed neutrophil apoptosis might enhance NET formation in ARDS. Method Our research was carried out in three aspects: clinical research, animal experiments, and in vitro experiments. First, we compared the difference between neutrophil apoptosis and NET levels in healthy controls and patients with ARDS and analyzed the correlation between neutrophil apoptosis and NET levels in ARDS. Then, we conducted animal experiments to verify the effect of neutrophil apoptosis on NET formation in Lipopolysaccharide-induced acute lung injury (LPS-ALI) mice. Furthermore, this study explored the relationship between neutrophil apoptosis and NETs at the cellular level. Apoptosis was assessed using morphological analysis, flow cytometry, and western blotting. NET formation was determined using immunofluorescence, PicoGreen assay, SYTOX Green staining, and western blotting. Results ARDS neutrophils lived longer because of delayed apoptosis, and the cyclin-dependent kinase inhibitor, AT7519, reversed this phenomenon both in ARDS neutrophils and neutrophils in bronchoalveolar lavage fluid (BALF) of LPS-ALI mice. Neutrophils in a medium containing pro-survival factors (LPS or GM-CSF) form more NETs, which can also be reversed by AT7519. Tissue damage can be reduced by promoting neutrophil apoptosis. Conclusions Neutrophils with extended lifespan in ARDS usually enhance NET formation, which aggravates inflammation. Enhancing neutrophil apoptosis in ARDS can reduce the formation of NETs, inhibit inflammation, and consequently alleviate ARDS.

show abstract

Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis

Cited by 100 publications

References 21 publications

Ageing and interferon gamma response drive the phenotype of neutrophils in the inflamed joint

Ageing and interferon gamma response drive the phenotype of neutrophils in the inflamed joint

Specific NLRP3 Inflammasome Assembling and Regulation in Neutrophils: Relevance in Inflammatory and Infectious Diseases

Delayed neutrophil apoptosis may enhance NET formation in ARDS

Contact Info

Product

Resources

About