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
  • 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. [email protected].
  • 8. John Radcliffe Hospital, Oxford Universities Hospitals NHS Foundation Trust, Oxford, UK. [email protected].
  • 9. NIHR Oxford Biomedical Research Centre, Oxford, UK. [email protected].
  • 10. Chinese Academy of Medical Science Oxford Institute, University of Oxford, Oxford, UK. [email protected].
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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