1. S100-alarmin-induced innate immune programming protects newborn infants from sepsis
- Author
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Maren von Köckritz-Blickwede, Lara Mellinger, Jennifer Schöning, Thomas Vogl, Constantin von Kaisenberg, Beate Fehlhaber, Johanna Burgmann, Friederike Reuner, Stefanie Zenker, Shirin Glander, Marie S Bickes, Johannes Roth, Katarzyna Barczyk-Kahlert, Joachim L. Schultze, Sandra Pfeifer, Thomas Ulas, Torsten G Loof, Anna S. Heinemann, Sabine Pirr, Martin Stanulla, Lena Völlger, Dorothee Viemann, Sabine Schreek, Judith Friesenhagen, and Lena Fischer-Riepe
- Subjects
0301 basic medicine ,Lipopolysaccharides ,immunology [Neonatal Sepsis] ,Lipopolysaccharide ,immunology [Calgranulin B] ,genetics [Myeloid Differentiation Factor 88] ,TICAM-1 protein, mouse ,Monocytes ,Epigenesis, Genetic ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,TICAM1 protein, human ,Immunology and Allergy ,immunology [Calgranulin A] ,Regulation of gene expression ,Mice, Knockout ,Neonatal sepsis ,genetics [Neonatal Sepsis] ,immunology [Toll-Like Receptor 4] ,Fetal Blood ,Flow Cytometry ,pharmacology [Lipopolysaccharides] ,drug effects [Monocytes] ,medicine.symptom ,Neonatal Sepsis ,genetics [Adaptor Proteins, Vesicular Transport] ,metabolism [Adaptor Proteins, Vesicular Transport] ,immunology [Adaptor Proteins, Vesicular Transport] ,Immunology ,drug effects [Immunity, Innate] ,Immunoblotting ,Inflammation ,Biology ,Real-Time Polymerase Chain Reaction ,Proinflammatory cytokine ,Sepsis ,03 medical and health sciences ,immunology [Monocytes] ,Immunity ,medicine ,Animals ,Calgranulin B ,Humans ,Calgranulin A ,ddc:610 ,Innate immune system ,Gene Expression Profiling ,drug effects [Calgranulin B] ,Infant, Newborn ,medicine.disease ,Immunity, Innate ,immunology [Immunity, Innate] ,Toll-Like Receptor 4 ,Adaptor Proteins, Vesicular Transport ,030104 developmental biology ,chemistry ,Animals, Newborn ,Gene Expression Regulation ,immunology [Myeloid Differentiation Factor 88] ,Myeloid Differentiation Factor 88 ,drug effects [Calgranulin A] ,030215 immunology - Abstract
The high risk of neonatal death from sepsis is thought to result from impaired responses by innate immune cells; however, the clinical observation of hyperinflammatory courses of neonatal sepsis contradicts this concept. Using transcriptomic, epigenetic and immunological approaches, we demonstrated that high amounts of the perinatal alarmins S100A8 and S100A9 specifically altered MyD88-dependent proinflammatory gene programs. S100 programming prevented hyperinflammatory responses without impairing pathogen defense. TRIF-adaptor-dependent regulatory genes remained unaffected by perinatal S100 programming and responded strongly to lipopolysaccharide, but were barely expressed. Steady-state expression of TRIF-dependent genes increased only gradually during the first year of life in human neonates, shifting immune regulation toward the adult phenotype. Disruption of this critical sequence of transient alarmin programming and subsequent reprogramming of regulatory pathways increased the risk of hyperinflammation and sepsis. Collectively these data suggest that neonates are characterized by a selective, transient microbial unresponsiveness that prevents harmful hyperinflammation in the delicate neonate while allowing for sufficient immunological protection.
- Published
- 2017
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