Neutrophil functional heterogeneity is a fixed phenotype and is associated with distinct gene expression profiles

McKelvy, Margaret; Boyle, Kimberly; Hotchkiss, Halie; Duarte, Madelaine; Addison, Bechtler; Amato, Nicholas; Khandelwal, Sanjay; Arepally, Gowthami M.; Lee, Grace M.

doi:10.1002/jlb.4a0322-164r

Cited by 8 publications

(10 citation statements)

References 45 publications

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“…Notably, these differences in neutrophils could also represent how tissue specificity impacts neutrophil heterogeneity and future work may address how neutrophil populations change in tissues in response to infection. Finally, functional profiling of human healthy donor neutrophils has also demonstrated potential links to gene expression from bulk RNA-sequencing (Maskarinec et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted November 1, 2022. ; https://doi.org/10. 1101/2022 During this time, they perform a variety of roles in the setting of injury and disease, and the loss of neutrophils is a significant risk factor for developing an invasive fungal infection. Here, we examined clonal neutrophils for evidence of functional heterogeneity in response to Candida spp.…”

Section: Introductionmentioning

confidence: 99%

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Predestined neutrophil heterogeneity in homeostasis varies in transcriptional and phenotypic response toCandida

Hopke

Viens

et al. 2022

Preprint

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Once perceived to be homogenous effector cells, neutrophils have since been shown to exhibit population heterogeneity. Here, we established an experimental model of clonal neutrophil heterogeneity using conditionally immortalized clonal granulocyte monocyte progenitors (GMPs) and their mature neutrophil progeny. Transcriptional and epigenetic profiling showed conserved genome-wide signatures of transcription and chromatin accessibility that were specific to individual GMP clones and their paired neutrophil progeny, suggesting that clone specificity is established as early as the GMP stage. Clone-specific genes in vital regulatory pathways were pre-programmed and exhibited delayed expression in the mature neutrophil stage. The clone specific gene expression in the mature neutrophils paired to enhancer activation in their parental GMPs. To determine whether transcriptional heterogeneity predicted the response to fungal pathogens, neutrophil clones were functionally profiled. Clones demonstrated heterogeneous responses to fungal pathogens in vitro and revealed neutrophil subsets with evidence for tailored functional responses to Candida spp. as well as specific transcriptional and epigenetic patterns that may explain these differences. Together, this work establishes that heterogenous GMP and neutrophil compartments exist under homeostatic conditions and that these represent predefined clusters that are uniquely adapted to control invasive fungal pathogens.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predestined neutrophil heterogeneity in homeostasis varies in transcriptional and phenotypic response toCandida

Hopke

Viens

et al. 2022

Preprint

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“…Neutrophils from two individuals clinically defined as healthy can exhibit considerable variability in the kinetics and intensity of antimicrobial defenses triggered by the same pathogen. A recent characterization of neutrophil functional heterogeneity in healthy individuals revealed that degranulation, oxidative burst activity, and NET formation varied among individuals and correlated with each other 95 . Individuals with highly reactive neutrophils (high responders), defined by their level of degranulation, NET formation and ROS production in response to S. aureus , E. coli and Candida albicans , remained constant over a period of at least 3 years.…”

Section: Clec12a In Health and Diseasementioning

confidence: 99%

“…Altered CLEC12A gene and/or protein expression is reported in a number of disease states, including Crohn's disease, 78 systemic lupus erythematosus, Behcet's disease, 92 gouty arthritis, 32,33 and rheumatoid arthritis (RA) 83,93,94 . In healthy individuals, the heterogeneity of CLEC12A gene and protein expression suggests a possible role in disease susceptibility and severity and is discussed below 95 . We also address animal studies that support a causative relationship between CLEC12A expression and inflammatory diseases.…”

Section: Clec12a In Health and Diseasementioning

confidence: 99%

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Understanding inhibitory receptor function in neutrophils through the lens of CLEC12A

McLeish

Fernandes

2022

Immunological Reviews

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The immune system uses innate and adaptive immune defense mechanisms to kill offending cells and organisms, eliminate cancer cells, and respond to endogenous danger signals, while limiting damage to self. 1 Thus, an immune system response, including that of neutrophils, must be tightly regulated in a context-dependent manner. This regulation requires systems that control the threshold to activating signals, the strength of the response, and the timing of response termination. 2 Neutrophils possess a combination of functions that enable them to respond rapidly and efficiently to signals generated by infection or cell injury. 3 They are capable of rapid mobility, are one of the most deformable of eukaryotic cells, and are highly proficient in phagocytosing foreign particles. Phagocytosis sequesters pathogens into restricted spaces away from normal tissue, termed phagolysosomes, where a toxic environment is created by introduction of antimicrobial peptides and proteases by fusion with intracellular granules, by hydrogen ion generation leading to a low pH, and by NADPH oxidase complex production of reactive oxygen species (ROS). These same antimicrobial agents can be directly released extracellularly or as constituents of neutrophil extracellular traps (NETs). Neutrophils are the first leukocytes recruited in large numbers from the circulation to a site of infection where these effector functions eradicate pathogens and contribute to tissue repair. 4 To avoid collateral damage that

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Decoding the biology and clinical implication of neutrophils in intracranial aneurysm

Ji,

Han,

Danyang Jie

et al. 2024

Ann Clin Transl Neurol

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ObjectiveAbundant neutrophils have been identified in both ruptured and unruptured intracranial aneurysm (IA) domes, with their function and clinical implication being poorly characterized.Materials and MethodsWe employed single‐cell RNA sequencing (scRNA‐Seq) datasets of both human and murine model, and external bulk mRNA sequencing datasets to thoroughly explore the features and functional heterogeneous of neutrophils infiltrating the IA dome.ResultsWe found that both unruptured and ruptured IA dome contain a substantial population of neutrophils, characterized by FCGR3B, G0S2, CSF3R, and CXCR2. These cells exhibited heterogeneity in terms of function and differentiation. Despite similar transcriptional activation, neutrophils in IA dome expressed a repertoire of gene programs that mimicked transcriptomic alterations observed from bone marrow to peripheral blood, showing self‐similarity. In addition, the recruitment of neutrophils in unruptured IA was primarily mediated by monocytes/macrophages, and once ruptured, both neutrophils, and a specific subset of inflammatory smooth muscle cells (SMCs) were involved in the process. The receiver operator characteristic curve (ROC) analysis indicated that distinct neutrophil subclusters were associated with IA formation and rupture, respectively. By reviewing current studies, we found that neutrophils play a detrimental role to IA wall integrity through secreting specific ligands, ferroptosis driven by ALOX5AP and PTGS2, and the formation of neutrophil extracellular traps (NETs) mediated by PADI4.InterpretationThis study delineated the biology and potential clinical implications of neutrophils in IA dome and provided a reliable basis for future researches.

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Neutrophil functional heterogeneity is a fixed phenotype and is associated with distinct gene expression profiles

Abstract: Differences in neutrophil functional capacity represent a fixed phenotype and are defined by distinct neutrophil gene expression profiles.

Cited by 8 publications

References 45 publications

Predestined neutrophil heterogeneity in homeostasis varies in transcriptional and phenotypic response toCandida

Predestined neutrophil heterogeneity in homeostasis varies in transcriptional and phenotypic response toCandida

Understanding inhibitory receptor function in neutrophils through the lens of CLEC12A

Decoding the biology and clinical implication of neutrophils in intracranial aneurysm

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