2. Academic Validation
  3. Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis

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

  • Nat Immunol. 2023 Apr 24. doi: 10.1038/s41590-023-01490-5.
Andrew J Kwok 1,  Alice Allcock 1,  Ricardo C Ferreira 1,  Eddie Cano-Gamez 1 2,  Madeleine Smee 1,  Katie L Burnham 2,  Yasemin-Xiomara Zurke 3,  Emergency Medicine Research Oxford (EMROx),  Stuart McKechnie 4,  Alexander J Mentzer 1 4 5,  Claudia Monaco 3,  Irina A Udalova 3,  Charles J Hinds 6,  John A Todd 1 5,  Emma E Davenport 2,  Julian C Knight 7 8 9 10
Affiliations

Affiliations

  • 1 Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 2 Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
  • 3 Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
  • 4 John Radcliffe Hospital, Oxford Universities Hospitals NHS Foundation Trust, Oxford, UK.
  • 5 NIHR Oxford Biomedical Research Centre, Oxford, UK.
  • 6 William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University, London, UK.
  • 7 Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. julian.knight@well.ox.ac.uk.
  • 8 John Radcliffe Hospital, Oxford Universities Hospitals NHS Foundation Trust, Oxford, UK. julian.knight@well.ox.ac.uk.
  • 9 NIHR Oxford Biomedical Research Centre, Oxford, UK. julian.knight@well.ox.ac.uk.
  • 10 Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK. julian.knight@well.ox.ac.uk.
PMID: 37095375 DOI: 10.1038/s41590-023-01490-5
Abstract

Sepsis arises from diverse and incompletely understood dysregulated host response processes following Infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b+ sepsis neutrophils inhibited proliferation and activation of CD4+ T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2+ immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe Infection.

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