SIGNR1 promotes immune dysfunction in systemic candidiasis by modulating neutrophil lifespan via T cell-derived histones and G-CSF

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-m...

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Published in:bioRxiv 2021-08
Main Authors: Ioannou, Marianna, Hoving, Dennis, Iker Valle Aramburu, De Vasconcelos, Nathalia M, Temkin, Mia I, Wang, Qian, Vernardis, Spyros, Demichev, Vadim, Theodora-Dorita Tsourouktsoglou, Boeing, Stefan, Goldstone, Robert, David, Sascha, Klaus Klaus Stahl, Bode, Christian, Ralser, Markus, Papagiannopoulos, Venizelos
Format: Article
Language:English
Subjects:
Apoptosis
Candidiasis
Cell death
Chromatin
Colonization
Granulocyte colony-stimulating factor
Histones
Leukocytes (neutrophilic)
Life span
Lymphocytes
Lymphocytes T
Macrophages
Neutrophils
Peroxidase
Sepsis
Spleen
Surface markers
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Summary: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 neutrophils. Consistently, either T cell deficiency or blocking SIGNR1, G-CSF and 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 Statement The authors have declared no competing interest. Footnotes * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE160301
DOI:10.1101/2021.08.09.455510