S100-alarmin-induced innate immune programming protects newborn infants from sepsis

• Published in: Nature immunology Vol. 18; no. 6; pp. 622 - 632
• Main Authors: Ulas, Thomas, Pirr, Sabine, Fehlhaber, Beate, Bickes, Marie S, Loof, Torsten G, Vogl, Thomas, Mellinger, Lara, Heinemann, Anna S, Burgmann, Johanna, Schöning, Jennifer, Schreek, Sabine, Pfeifer, Sandra, Reuner, Friederike, Völlger, Lena, Stanulla, Martin, von Köckritz-Blickwede, Maren, Glander, Shirin, Barczyk-Kahlert, Katarzyna, von Kaisenberg, Constantin S, Friesenhagen, Judith, Fischer-Riepe, Lena, Zenker, Stefanie, Schultze, Joachim L, Roth, Johannes, Viemann, Dorothee
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.06.2017
• Subjects: Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - immunology; Adaptor Proteins, Vesicular Transport - metabolism; Animals; Animals, Newborn; Calgranulin A - drug effects; Calgranulin A - immunology; Calgranulin B - drug effects; Calgranulin B - immunology; Cellular proteins; Death; Epigenesis, Genetic; Epigenetics; Fetal Blood; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation; Genetic aspects; Health aspects; Humans; Immune response; Immunity, Innate - drug effects; Immunity, Innate - immunology; Immunoblotting; Immunology; Immunoregulation; Infant, Newborn; Infants; Inflammation; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Mice; Mice, Knockout; Microorganisms; Monocytes - drug effects; Monocytes - immunology; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Neonatal Sepsis - genetics; Neonatal Sepsis - immunology; Neonates; Newborn infants; Pathogens; Prevention; Real-Time Polymerase Chain Reaction; Regulatory sequences; Sepsis; Toll-Like Receptor 4 - immunology
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3745

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.