Microbe capture by splenic macrophages triggers sepsis via T cell-death-dependent neutrophil lifespan shortening

Marianna Ioannou, Dennis Hoving, Iker Valle Aramburu, Mia I. Temkin, Nathalia M. Vasconcelos, Theodora-Dorita Tsourouktsoglou, Qian Wang, Stefan Boeing, Robert Goldstone, Spyros Vernardis, Vadim Demichev, Markus Ralser, Sascha David, Klaus Stahl, Christian Bode and Venizelos Papayannopoulos ()
Additional contact information
Marianna Ioannou: Antimicrobial Defence Laboratory
Dennis Hoving: Antimicrobial Defence Laboratory
Iker Valle Aramburu: Antimicrobial Defence Laboratory
Mia I. Temkin: Antimicrobial Defence Laboratory
Nathalia M. Vasconcelos: Antimicrobial Defence Laboratory
Theodora-Dorita Tsourouktsoglou: Antimicrobial Defence Laboratory
Qian Wang: Antimicrobial Defence Laboratory
Stefan Boeing: Bioinformatics and Biostatistics
Robert Goldstone: Advanced Sequencing
Spyros Vernardis: Molecular Biology of Metabolism Laboratory
Vadim Demichev: Molecular Biology of Metabolism Laboratory
Markus Ralser: Molecular Biology of Metabolism Laboratory
Sascha David: University Hospital Zurich
Klaus Stahl: Hepatology and Endocrinology, Medical School Hannover
Christian Bode: University Hospital Bonn
Venizelos Papayannopoulos: Antimicrobial Defence Laboratory

Nature Communications, 2022, vol. 13, issue 1, 1-24

Abstract: Abstract The mechanisms linking systemic infection to hyperinflammation and immune dysfunction in sepsis are poorly understood. Extracellular histones promote sepsis pathology, but their source and mechanism of action remain unclear. Here, we show that by controlling fungi and bacteria captured by splenic macrophages, neutrophil-derived myeloperoxidase attenuates sepsis by suppressing histone release. In systemic candidiasis, microbial capture via the phagocytic receptor SIGNR1 neutralizes myeloperoxidase by facilitating marginal zone infiltration and T cell death-dependent histone release. Histones and hyphae induce cytokines in adjacent CD169 macrophages including G-CSF that selectively depletes mature Ly6Ghigh neutrophils by shortening their lifespan in favour of immature Ly6Glow neutrophils with a defective oxidative burst. In sepsis patient plasma, these mediators shorten mature neutrophil lifespan and correlate with neutrophil mortality markers. Consequently, high G-CSF levels and neutrophil lifespan shortening activity are associated with sepsis patient mortality. Hence, by exploiting phagocytic receptors, pathogens degrade innate and adaptive immunity through the detrimental impact of downstream effectors on neutrophil lifespan.

Date: 2022
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DOI: 10.1038/s41467-022-32320-1

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