PT  - JOURNAL ARTICLE
AU  - Marianna Ioannou
AU  - Dennis Hoving
AU  - Iker Valle Aramburu
AU  - Nathalia M. De Vasconcelos
AU  - Mia I. Temkin
AU  - Qian Wang
AU  - Spyros Vernardis
AU  - Vadim Demichev
AU  - Theodora-Dorita Tsourouktsoglou
AU  - Stefan Boeing
AU  - Robert Goldstone
AU  - Sascha David
AU  - Klaus Stahl
AU  - Christian Bode
AU  - Markus Ralser
AU  - Venizelos Papayannopoulos
TI  - SIGNR1 promotes immune dysfunction in systemic candidiasis by modulating neutrophil lifespan via T cell-derived histones and G-CSF
AID  - 10.1101/2021.08.09.455510
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.08.09.455510
4099  - http://biorxiv.org/content/early/2021/08/19/2021.08.09.455510.short
4100  - http://biorxiv.org/content/early/2021/08/19/2021.08.09.455510.full
AB  - The mechanisms regulating immune dysfunction during sepsis are poorly understood. Here, we show that neutrophil-derived myeloperoxidase delays the onset of immune dysfunction during systemic candidiasis by controlling microbes captured by splenic marginal zone (MZ) macrophages. In contrast, SIGNR1-mediated microbe capture accelerates MZ colonization and immune dysfunction by triggering T cell death, T cell-dependent chromatin release and the synergistic induction of G-CSF by histones and fungi. Histones and G-CSF promote the prevalence of immature Ly6Glow neutrophils with defective oxidative burst, by selectively shortening the lifespan of mature Ly6Ghigh neutrophils. Consistently, T cell deficiency, or blocking SIGNR1, G-CSF or histones delayed neutrophil dysfunction. Furthermore, histones and G-CSF in the plasma of sepsis patients, shortened neutrophil lifespan and correlated with neutrophil mortality markers associated with a poor prognosis. Hence, the compromise of internal antimicrobial barrier sites drives neutrophil dysfunction by selectively modulating neutrophil lifespan via pathogenic T cell death, extracellular histones, and G-CSF.Competing Interest StatementThe authors have declared no competing interest.