Neutrophil Heterogeneity as Therapeutic Opportunity in Immune-Mediated Disease

Grieshaber-Bouyer, Ricardo; Nigrović, Peter A.

doi:10.3389/fimmu.2019.00346

Cited by 104 publications

(103 citation statements)

References 193 publications

(233 reference statements)

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“…Previous studies, including those from our own group, have already suggested a role for neutrophils in autoimmunity ( 12 – 14 ) and highlight context-specific diversity in neutrophil identity, plasticity, and function ( 15 ). Neutrophil heterogeneity is now a recognized phenomenon associated closely with several diseases.…”

Section: Introductionmentioning

confidence: 70%

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ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

Wang

Khoyratty

et al. 2020

JCI Insight

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Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b + CD15 + CD10 lo/– CD64 – band neutrophils and CD66b hi CD15 + CD10 lo/– CD64 +/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.

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Section: Introductionmentioning

confidence: 70%

“…Neutrophil heterogeneity is now a recognized phenomenon associated closely with several diseases. However, evidence of unequivocal characterization of bona fide neutrophil subsets, particularly in the context of pathological conditions, has not yet been reported, to our knowledge ( 14 – 16 ).…”

Section: Introductionmentioning

confidence: 93%

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

Wang

Khoyratty

et al. 2020

JCI Insight

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“…Neutrophil heterogeneity can be phenotypic or functional and is pronounced at different levels of their life cycle, either in homeostatic or disease conditions (13,28). Infectious inflammation can induce rapid changes in neutrophil variants as a function of maturity or activation state (11,28). While the innate immune response is the initial responders to infection, the other cellular response are also important.…”

Section: Discussionmentioning

confidence: 99%

“…The ectodomain shedding of CD62L from neutrophil plasma membrane denotes neutrophil activation or partial activation (priming), concordant with upregulation of CD11b, a component of the macrophage-1 antigen (Mac-1) (CD11b/CD18) β 2 -integrin subfamily (9). Appearance of the surface marker, CD54, on activated neutrophils correlates with reverse transendothelial migration, and its expression is known to be increased by inflammatory stimuli (10,11). Neutrophils showing antitumorigenic phenotypes show increased CD54 expression (12), while CD54 expressing neutrophils are also associated with chronic systemic inflammation (13).…”

Section: Introductionmentioning

confidence: 88%

Distinct Neutrophil Populations in the Spleen During PICS

2020

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While mortality after acute sepsis has decreased, the long-term recovery for survivors is still poor, particularly those developing persistent inflammation, immunosuppression, and catabolism syndrome (PICS). While previously thought that activated neutrophils responding to the acute phase of sepsis migrate to the spleen to undergo cell death and contribute to immunosuppression, our data show a significant accumulation of distinct, yet functional, neutrophil populations in the spleen in a murine model of PICS. The exact role and function of neutrophils in this response is still unclear. The objective of our study was to better define the immune function of splenic neutrophils to determine if this could give insight into the pathogenesis of PICS. Using a murine model of cecal ligation and puncture (CLP), which demonstrates all characteristics of PICS by 8 days, spleens were harvested, and neutrophils were identified by Ly6G and CD11b expression via flow cytometry. Nearly all splenic neutrophils expressed CD54, but there were distinct CD54 hi and CD54 lo cells, with the majority being CD54 lo cells during PICS. The CD54 hi population showed traditional, proinflammatory properties, but a relatively decreased chemotactic response, while CD54 lo cells had significantly higher chemotaxis, yet significantly decreased proinflammatory functions. Using 5-ethynyl-2 ′-deoxyuridine (EdU) incorporation, we found that the CD54 hi population on day 2 after CLP may be participating in emergency myelopoiesis. However, the vast majority of the CD54 lo population were paused in the G 1 phase at this time point and not proliferating. By day 8 after CLP, most of the CD54 hi cells in the spleen were no longer proliferating, while the CD54 lo cells were, indicating that CD54 lo dominate in extramedullary myelopoiesis at later time points. Almost none of the neutrophils produced arginase or inducible nitric oxide synthase (iNOS), indicating that these are not suppressor cells. Overall, our data demonstrate that neutrophil accumulation in the spleen during PICS is related to extramedullary myelopoiesis, leading to the production of immature neutrophils. While not suppressor cells, the majority have greater chemotactic function but less inflammatory responsiveness, which may contribute to the immunosuppression seen in PICS. Attention to these distinct neutrophil populations after septic or other systemic inflammatory responses is therefore critical to understanding the mechanisms of PICS.

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“…In vivo interference with the production of neutrophil extracellular traps (NETs) has been shown to be protective in systemic lupus erythematosus (SLE) (73) and transfusion-related acute lung injury (TRALI) (74), whereas the β1-adrenergic-receptor antagonist metoprolol decreases infarct size during AMI by interfering neutrophil recruitment and neutrophil-platelet interactions (75). These and other examples postulate the possibility to target neutrophils therapeutically, as reviewed recently (76,77). Given the observation that the molecular clock influences the effector functions of neutrophils, an outstanding question is whether this "neutrophil clock" can be targeted to prevent inflammatory disease.…”

Section: Targeting the Circadian Properties Of Neutrophils For Therapymentioning

confidence: 99%

Circadian Features of Neutrophil Biology

2020

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Rhythms in immunity manifest in multiple ways, but perhaps most prominently by the recurrent onset of inflammation at specific times of day. These patterns are of importance to understand human disease and are caused, in many instances, by the action of neutrophils, a myeloid leukocyte with striking circadian features. The neutrophil's short life, marked diurnal variations in number, and changes in phenotype while in the circulation, help explain the temporal features of inflammatory disease but also uncover core features of neutrophil physiology. Here, we summarize well-established concepts and introduce recent discoveries in the biology of these cells as they relate to circadian rhythms. We highlight that although the circadian features of neutrophils are better known and relevant to understand disease, they may also influence important aspects of organ function even in the steady-state. Finally, we discuss the possibility of targeting these temporal features of neutrophils for therapeutic benefit.

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Neutrophil Heterogeneity as Therapeutic Opportunity in Immune-Mediated Disease

Cited by 104 publications

References 193 publications

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

Distinct Neutrophil Populations in the Spleen During PICS

Circadian Features of Neutrophil Biology

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