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

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journal contribution
posted on 2022-08-12, 11:08 authored by Marianna Ioannou, Dennis Hoving, Iker Valle Aramburu, Mia I Temkin, Nathalia M De Vasconcelos, Theodora Dorita Tsourouktsoglou, Qian Wang, Stefan Boeing, Robert Goldstone, Spyros Vernardis, Vadim Demichev, Markus Ralser, Sascha David, Klaus Stahl, Christian Bode, Venizelos Papayannopoulos
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.

Funding

Crick (Grant ID: 10129, Grant title: Papayannopoulos FC001129) Crick (Grant ID: 10134, Grant title: Ralser FC001134) Crick (Grant ID: 10001, Grant title: STP Advanced Sequencing) Crick (Grant ID: CC1107, Grant title: STP Bioinformatics & Biostatistics)

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