Two New Neutrophil Subsets Define a Discriminating Sepsis Signature

Meghraoui-Kheddar, Aïda; Chousterman, Benjamin; Guillou, Noëlline; Barone, Sierra; Granjeaud, Samuel; Vallet, Hélène; Corneau, Aurélien; Guessous, Karim; Roquetaillade, Charles de; Boissonnas, Alexandre; Irish, Jonathan M.; Combadière, Christophe

doi:10.1164/rccm.202104-1027oc

Cited by 38 publications

(38 citation statements)

References 41 publications

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“…In contrast to previous reports (7), when we subjected the neutrophils to other functional tests, we found that cell-intrinsic functions of sepsis neutrophils were intact, with preserved phagocytic activity and ROS production (Figs. S4E-F).…”

Section: Sepsis Neutrophils Show Cd4 T Cell Immunosuppressive Capacitycontrasting

confidence: 99%

“…S4A-C). Increased arginase-1 activity and PD-L1/2 inhibition of T cells have been proposed as mechanisms for neutrophil immunosuppression (7,8), but we were unable to reverse the suppressive effects with either anti-PDL1/2 antibodies or arginase-1 inhibitors (Fig. S4D).…”

Section: Sepsis Neutrophils Show Cd4 T Cell Immunosuppressive Capacitymentioning

confidence: 78%

“…However, there has been a lack of high resolution single-cell transcriptomic readouts inclusive of granulocytes, which form the majority of peripheral blood leukocytes, leading to a disconnect in interpreting single-cell PBMC vs. whole blood bulk transcriptomic data. As the first line of defense against pathogens, neutrophils have been demonstrated through peripheral blood immunophenotyping to be differentially abundant between sepsis and non-infectious inflammation (7). In sepsis patients, expansion of immunosuppressive granulocytes has been associated with a higher risk of nosocomial infection (8).…”

Section: Introductionmentioning

confidence: 99%

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Identification of deleterious neutrophil states and altered granulopoiesis in sepsis

Kwok

Allcock

Ferreira

et al. 2022

Preprint

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Sepsis is a condition of high mortality arising from dysregulation of the host immune response. Gene expression studies have identified multiple immune endotypes but gaps remain in our understanding of the underlying biology and heterogeneity. We used single-cell multi-omics to profile 272,993 cells across 48 whole blood samples from 26 sepsis patients (9 with paired convalescent samples), 6 healthy controls and 7 post-surgery patients. We identified immature neutrophil populations specific to sepsis and demonstrated the immunosuppressive nature of sepsis neutrophils in vitro. An IL1R2+ neutrophil state was expanded in a transcriptomic sepsis endotype associated with increased early mortality (sepsis response signature 1, SRS1), together with enrichment of the response to IL-1 pathway in mature neutrophils, marking IL-1 out as a potential target for immunotherapy in SRS1 sepsis patients. We confirmed the expansion of immature neutrophils, specifically IL1R2+ neutrophils, in SRS1 in additional cohorts of patients (n = 906 RNA-sequencing samples, n = 41 CyTOF samples). Neutrophil changes persisted in convalescence, implicating disrupted granulopoiesis. Our findings establish a cellular immunological basis for transcriptomically defined sepsis endotypes and emphasise the relevance of granulopoietic dysfunction in sepsis, identifying opportunities for precision medicine approaches to the condition.

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Section: Sepsis Neutrophils Show Cd4 T Cell Immunosuppressive Capacitycontrasting

confidence: 99%

Section: Sepsis Neutrophils Show Cd4 T Cell Immunosuppressive Capacitymentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

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Identification of deleterious neutrophil states and altered granulopoiesis in sepsis

Kwok

Allcock

Ferreira

et al. 2022

Preprint

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“…CD10 was suggested as a marker to distinguish proinflammatory and immunosuppressive neutrophils within heterogeneous neutrophil populations in patients with acute or chronic inflammatory diseases ( 77 ). A recent study has identified two neutrophil subsets, CD123 + immature neutrophils and programmed death-ligand 1 (PD-L1) + /CD10 - neutrophils as potential biomarkers for patients with sepsis ( 78 ). Future studies are needed to elucidate the contribution of these subsets to the pathogenesis of sepsis.…”

Section: Neutrophils In Homeostasis and Pathogenesismentioning

confidence: 99%

Targeting Neutrophils for Promoting the Resolution of Inflammation

Filep

2022

Front. Immunol.

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Acute inflammation is a localized and self-limited innate host-defense mechanism against invading pathogens and tissue injury. Neutrophils, the most abundant immune cells in humans, play pivotal roles in host defense by eradicating invading pathogens and debris. Ideally, elimination of the offending insult prompts repair and return to homeostasis. However, the neutrophils` powerful weaponry to combat microbes can also cause tissue damage and neutrophil-driven inflammation is a unifying mechanism for many diseases. For timely resolution of inflammation, in addition to stopping neutrophil recruitment, emigrated neutrophils need to be disarmed and removed from the affected site. Accumulating evidence documents the phenotypic and functional versatility of neutrophils far beyond their antimicrobial functions. Hence, understanding the receptors that integrate opposing cues and checkpoints that determine the fate of neutrophils in inflamed tissues provides insight into the mechanisms that distinguish protective and dysregulated, excessive inflammation and govern resolution. This review aims to provide a brief overview and update with key points from recent advances on neutrophil heterogeneity, functional versatility and signaling, and discusses challenges and emerging therapeutic approaches that target neutrophils to enhance the resolution of inflammation.

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“…In this issue of the Journal , Meghraoui-Kheddar and colleagues (pp. 46–59 ) used a high-dimensional mass cytometry approach for an in-depth and single-cell immune profile comparing patients with sepsis with those with sterile inflammation ( 8 ). Using a state-of-the-art unsupervised analysis to capture the cellular diversity of the neutrophil compartment, the authors identified and prospectively validated a neutrophil immunological signature that accurately differentiates patients with sepsis from control subjects.…”

mentioning

confidence: 99%