RT Journal Article
SR Electronic
T1 SIGNR1 promotes immune dysfunction in systemic candidiasis by modulating neutrophil lifespan via T cell-derived histones and G-CSF
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.09.455510
DO 10.1101/2021.08.09.455510
A1 Marianna Ioannou
A1 Dennis Hoving
A1 Iker Valle Aramburu
A1 Nathalia M. De Vasconcelos
A1 Mia I. Temkin
A1 Qian Wang
A1 Spyros Vernardis
A1 Vadim Demichev
A1 Theodora-Dorita Tsourouktsoglou
A1 Stefan Boeing
A1 Robert Goldstone
A1 Sascha David
A1 Klaus Stahl
A1 Christian Bode
A1 Markus Ralser
A1 Venizelos Papayannopoulos
YR 2021
UL http://biorxiv.org/content/early/2021/08/19/2021.08.09.455510.abstract
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.