title: In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock.
abstract: The high susceptibility of newborn infants to sepsis is ascribed to an immaturity of the neonatal immune system, but the molecular mechanisms remain unclear. Newborn monocytes massively release the alarmins S100A8/S100A9. In adults, these are major regulators of immunosuppressive myeloid-derived suppressor cells (MDSCs). We investigated whether S100A8/S100A9 cause an expansion of monocytic MDSCs (Mo-MDSCs) in neonates, thereby contributing to an immunocompromised state. Mo-MDSCs have been assigned to CD14+/human leukocyte antigen (HLA)-DR-/low/CD33+monocytes in humans and to CD11b+/Gr-1int/Ly6G-/Ly6Chicells in mice. We found monocytes with these phenotypes significantly expanded in their respective newborns. Functionally, however, they did not prove immunosuppressive but rather responded inflammatorily to microbial stimulation. Their expansion did not correlate with high S100A8/S100A9 levels in cord blood. Murine studies revealed an excessive expansion of CD11b+/Gr-1int/Ly6G-/Ly6Chimonocytes in S100A9-/-neonates compared to wild-type neonates. This strong baseline expansion was associated with hyperinflammatory responses during endotoxemia and fatal septic courses. Treating S100A9-/-neonates directly after birth with S100A8/S100A9 alarmins prevented excessive expansion of this inflammatory monocyte population and death from septic shock. Our data suggest that a specific population of inflammatory monocytes promotes fatal courses of sepsis in neonates if its expansion is not regulated by S100A8/S100A9 alarmins.-Heinemann, A. S., Pirr, S., Fehlhaber, B., Mellinger, L., Burgmann, J., Busse, M., Ginzel, M., Friesenhagen, J., von Köckritz-Blickwede, M., Ulas, T., von Kaisenberg, C. S., Roth, J., Vogl, T., Viemann, D. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock.
authors.affiliation: Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Heinemann
authors.affiliation: Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Pirr
authors.affiliation: Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Fehlhaber
authors.affiliation: Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Lara
authors.initials: L
authors.lastname: Mellinger
authors.affiliation: Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Burgmann
authors.affiliation: Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Busse
authors.affiliation: Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Ginzel
authors.affiliation: Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Friesenhagen
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.|Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: von Köckritz-Blickwede
authors.affiliation: Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulas
authors.affiliation: Department of Gynecology and Prenatal Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Constantin S
authors.initials: CS
authors.lastname: von Kaisenberg
authors.affiliation: Institute of Immunology, University of Münster, Münster, Germany.|Interdisciplinary Centre for Clinical Research, University of Münster, Münster, Germany; and.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Institute of Immunology, University of Münster, Münster, Germany.|Interdisciplinary Centre for Clinical Research, University of Münster, Münster, Germany; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany; viemann.dorothee@mh-hannover.de.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Viemann
mesh_terms: D000067531:Alarmins / Q000097:blood*; D000818:Animals; D040501:Calgranulin A / Q000097:blood* / Q000627:therapeutic use; D040502:Calgranulin B / Q000097:blood* / Q000627:therapeutic use; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology*; D000071074:Neonatal Sepsis / Q000097:blood* / Q000517:prevention & control; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000235:genetics / Q000378:metabolism
chemical_list: D000067531:Alarmins; D040501:Calgranulin A; D040502:Calgranulin B; D018950:Lipopolysaccharide Receptors; D063268:Sialic Acid Binding Ig-like Lectin 3
keywords: MDSC; calprotectin; myeloid cells; newborn; sepsis