Abstract Programmed death ligand 1 (PD-L1) has been shown to be inducibly expressed on neutrophils to suppress host immunity during polymicrobial sepsis, virus and parasite infections. However, the role of PD-L1 on neutrophil-mediated antifungal immunity remains wholly unknown. Here, we show that the expression of PD-L1 on murine and human neutrophils was upregulated upon the engagement of C-type lectin receptor Dectin-1 with its ligand β-glucans, exposed on fungal pathogen Candida albicans yeast. Moreover, β-glucan stimulation induced PD-L1 translocation into nucleus to regulate the production of chemokines CXCL1 and CXCL2, which control neutrophil mobilization. Importantly, C. albicans infection-induced expression of PD-L1 leads to neutrophil accumulation in bone marrow, through mediating their autocrine secretion of CXCL1/2. Furthermore, neutrophil-specific deficiency of PD-L1 impaired CXCL1/2 secretion, which promoted neutrophil migration from bone marrow into the peripheral circulation, thereby conferring host resistance to C. albicans infection. Finally, either PD-L1 blockade or pharmacological inhibition of PD-L1 expression significantly increased neutrophil release from bone marrow to enhance host antifungal immunity. Our data together indicate that activation of Dectin-1/PD-L1 cascade by β-glucans inhibits neutrophil release from bone marrow reserve, contributing to the negative regulation of antifungal innate immunity, which functions as a potent immunotherapeutic target against life-threatening fungi infections. 

/pdf/pd-l1-negatively-regulates-antifungal-immunity-by-inhibiting-h6lmchy1.pdf

PD-L1 negatively regulates antifungal immunity by inhibiting neutrophil release from bone marrow

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.

/pdf/specific-nlrp3-inflammasome-assembling-and-regulation-in-2kobyi44.pdf

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

PD-1/PD-L1 blockade is a potent adjuvant in treatment of Staphylococcus aureus osteomyelitis in mice.

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 in vivo and in vitro. 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.

/pdf/pd-l1-maintains-neutrophil-extracellular-traps-release-by-1825i5uk.pdf

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

Deep tissue infection is a common clinical issue and therapeutic difficulty caused by the disruption of the host antibacterial immune function, resulting in treatment failure and infection relapse. Intracellular pathogens are refractory to elimination and can manipulate host cell biology even after appropriate treatment, resulting in a locoregional immunosuppressive state that leads to an inadequate response to conventional anti‐infective therapies. Here, a novel antibacterial strategy involving autogenous immunity using a biomimetic nanoparticle (NP)‐based regulating system is reported to induce in situ collaborative innate–adaptive immune responses. It is observed that a macrophage membrane coating facilitates NP enrichment at the infection site, followed by active NP accumulation in macrophages in a mannose‐dependent manner. These NP‐armed macrophages exhibit considerably improved innate capabilities, including more efficient intracellular ROS generation and pro‐inflammatory factor secretion, M1 phenotype promotion, and effective eradication of invasive bacteria. Furthermore, the reprogrammed macrophages direct T cell activation at infectious sites, resulting in a robust adaptive antimicrobial immune response to ultimately achieve bacterial clearance and prevent infection relapse. Overall, these results provide a conceptual framework for a novel macrophage‐based strategy for infection treatment via the regulation of autogenous immunity.

An On-Demand Collaborative Innate-Adaptive Immune Response to Infection Treatment.

The underlying mechanisms contributing to injury-induced infection susceptibility remain poorly understood. Here, we describe a rapid increase in neutrophil cell numbers in the lungs following induction of thermal injury. These neutrophils expressed elevated levels of programmed death ligand 1 (PD-L1) and exhibited altered gene expression profiles indicative of a reparative population. Upon injury, neutrophils migrate from the bone marrow to the skin but transiently arrest in the lung vasculature. Arrested neutrophils interact with programmed cell death protein 1 (PD-1) on lung endothelial cells. A period of susceptibility to infection is linked to PD-L1+ neutrophil accumulation in the lung. Systemic treatment of injured animals with an anti-PD-L1 antibody prevented neutrophil accumulation in the lung and reduced susceptibility to infection but augmented skin healing, resulting in increased epidermal growth. This work provides evidence that injury promotes changes to neutrophils that are important for wound healing but contribute to infection susceptibility.

https://advances.sciencemag.org/content/advances/7/10/eabd9436.full.pdf

PD-L1 + neutrophils contribute to injury-induced infection susceptibility.

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PD-L1 + neutrophils contribute to injury-induced infection susceptibility.