Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis

Kwok, Andrew; Allcock, Alice; Ferreira, Ricardo C.; Cano-Gamez, Eddie; Smee, Madeleine; Burnham, Katie L; Zurke, Yasemin-Xiomara; Novak, Alex; Darwent, Melanie; Baron, Tanya; Brown, Charlotte; Beer, Sally; Espinosa, Alexis; Panduro, Tine; Georgiou, Dominique; Martinez, Jose; Thraves, Hannah; Perez, Elena; Fernández, Rocío; Sobrino, Alberto; Sánchez, Verónica; Magallano, Rufino; Dineen, Karen; Wilson, Jean; McKechnie, Stuart; Mentzer, Alexander J.; Monaco, Claudia; Udalova, Irina A.; Hinds, C. J.; Todd, John A.; Davenport, Emma E; Knight, Julian C.

doi:10.1038/s41590-023-01490-5

Cited by 75 publications

(71 citation statements)

References 80 publications

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“…To investigate this possibility, neutrophils were isolated from the peripheral blood of CRSwNP patients and cultured in specific medium at 37 °C. 43 Simultaneously, BEAS-2B cells were incubated with LPS or HDM for 12 h, followed by replacement of the supernatant with fresh medium and an additional 12 h incubation to mitigate potential interference of LPS and HDM in the subsequent experiments. The conditioned medium was collected and used to treat neutrophils, and the formation of NETs was observed using CitH3 staining.…”

Section: Resultsmentioning

confidence: 99%

Tackling Severe Neutrophilic Inflammation in Airway Disorders with Functionalized Nanosheets

Tu,

Zhu,

Gao

et al. 2024

ACS Nano

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Severe airway inflammatory disorders impose a significant societal burden, and the available treatments are unsatisfactory. High levels of neutrophil extracellular trap (NET) and cell-free DNA (cfDNA) were detected in the inflammatory microenvironment of these diseases, which are closely associated with persistent uncontrolled neutrophilic inflammation. Although DNase has proven to be effective in mitigating neutrophilic airway inflammation in mice by reducing cfDNA and NET levels, its clinical use is hindered by severe side effects. Here, we synthesized polyglycerol-amine (PGA) with a series of hydroxyl/amine ratios and covered them with black phosphorus (BP) nanosheets. The BP nanosheets functionalized with polyglycerol-50% amine (BP-PGA 50 ) efficiently lowered cfDNA levels, suppressed tolllike receptor 9 (TLR9) activation and inhibited NET formation in vitro. Importantly, BP-PGA 50 nanosheets demonstrated substantial accumulation in inflamed airway tissues, excellent biocompatibility, and potent inflammation modulation ability in model mice. The 2D sheet-like structure of BP-PGA 50 was identified as a crucial factor for the therapeutic efficacy, and the hydroxyl/amine ratio was revealed as a significant parameter to regulate the protein resistance, cfDNA-binding efficacy, and cytotoxicity. This study shows the promise of the BP-PGA 50 nanosheet for tackling uncontrolled airway inflammation, which is also significant for the treatment of other neutrophilic inflammatory diseases. In addition, our work also highlights the importance of proper surface functionalization, such as hydroxyl/amine ratio, in therapeutic nanoplatform construction for inflammation modulation.

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Section: Resultsmentioning

confidence: 99%

Tackling Severe Neutrophilic Inflammation in Airway Disorders with Functionalized Nanosheets

Tu,

Zhu,

Gao

et al. 2024

ACS Nano

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“…The pathophysiology and clinical manifestations of sepsis are heterogenous, highlighting the need for biomarkers of patient subgroups that could benefit from targeted therapies. In this issue of Nature Immunology, Kwok et al 2 combine single-cell genomics with clinical information to map aberrant granulopoiesis in human sepsis. The authors uncover subsets of neutrophils with immunosuppressive capacities, and delineate specific molecular signatures in individuals with poor outcomes.…”

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confidence: 99%

“…Kwok et al 2 generate an atlas of both scRNA-seq and surface protein expression for more than 250,000 blood leukocytes from septic or convalescent individuals, as well as healthy donors or people undergoing cardiac surgery. The authors detected a broad increase in neutrophil abundance and diversity in sepsis, reflecting heightened synthesis and release into the circulation of cells lacking terminal differentiation markers during emergency granulopoiesis.…”

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confidence: 99%

“…The findings of Kwok et al 2 raise several exciting questions. It will be interesting to elucidate how, mechanistically, the identified networks of cytokines and transcription factors orchestrate the phenotypic, molecular and functional (immunosuppressive) properties of neutrophils in people with sepsis; whether there are dedicated differentiation programs connecting sepsis-elicited subsets of HSCs and IL-1R2 + neutrophils in high-risk individuals; what is the fate of sepsis-associated neutrophils upon their exit from the circulation and subgroups of individuals with viral (SARS-CoV2 or influenza) or bacterial (fecal peritonitis) infections, community-acquired pneumonia, acute respiratory distress syndrome (ARDS) or pediatric sepsis.…”

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confidence: 99%

“…1 | Granulopoietic disturbances in high-risk and convalescent sepsis patients. Kwok et al2 have generated a combined atlas of scRNA-seq and surface protein expression for leukocytes from septic and convalescent individuals, healthy donors and people undergoing cardiac surgery. a, Multiple subsets of immature neutrophils (PADI4 + , MPO + and MKI67 + CYP1B1 + Neu) with immunosuppressive capacity are found in the blood of people with sepsis (both non-SRS1 and SRS1), concomitant with the emergence of a neutrophil-primed cluster (defined as C7) of HSCs with a CEBPA signature.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Charting granulopoietic disturbances in sepsis

Barouni

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2023

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Physiological and immunological barriers in the lung

Kageyama,

Ito,

Tanaka

et al. 2024

Semin Immunopathol

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The lungs serve as the primary organ for respiration, facilitating the vital exchange of gases with the bloodstream. Given their perpetual exposure to external particulates and pathogens, they possess intricate protective barriers. Cellular adhesion in the lungs is robustly maintained through tight junctions, adherens junctions, and desmosomes. Furthermore, the pulmonary system features a mucociliary clearance mechanism that synthesizes mucus and transports it to the outside. This mucus is enriched with chemical barriers like antimicrobial proteins and immunoglobulin A (IgA). Additionally, a complex immunological network comprising epithelial cells, neural cells, and immune cells plays a pivotal role in pulmonary defense. A comprehensive understanding of these protective systems offers valuable insights into potential pathologies and their therapeutic interventions.

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Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis

Cited by 75 publications

References 80 publications

Tackling Severe Neutrophilic Inflammation in Airway Disorders with Functionalized Nanosheets

Tackling Severe Neutrophilic Inflammation in Airway Disorders with Functionalized Nanosheets

Charting granulopoietic disturbances in sepsis

Physiological and immunological barriers in the lung

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