PMID- 27993995 OWN - NLM STAT- MEDLINE DCOM- 20170906 LR - 20171227 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 31 IP - 3 DP - 2017 Mar TI - In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. PG - 1153-1164 LID - 10.1096/fj.201601083R [doi] AB - 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-1(int)/Ly6G(-)/Ly6C(hi) cells 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-1(int)/Ly6G(-)/Ly6C(hi) monocytes 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 Kockritz-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. CI - (c) FASEB. FAU - Heinemann, Anna S AU - Heinemann AS AD - Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany. FAU - Pirr, Sabine AU - Pirr S AD - Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany. FAU - Fehlhaber, Beate AU - Fehlhaber B AD - Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany. FAU - Mellinger, Lara AU - Mellinger L AD - Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany. FAU - Burgmann, Johanna AU - Burgmann J AD - Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany. FAU - Busse, Mandy AU - Busse M AD - Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany. FAU - Ginzel, Marco AU - Ginzel M AD - Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany. FAU - Friesenhagen, Judith AU - Friesenhagen J AD - Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany. FAU - von Kockritz-Blickwede, Maren AU - von Kockritz-Blickwede M AD - Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany. AD - Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany. FAU - Ulas, Thomas AU - Ulas T AD - Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany. FAU - von Kaisenberg, Constantin S AU - von Kaisenberg CS AD - Department of Gynecology and Prenatal Medicine, Hannover Medical School, Hannover, Germany. FAU - Roth, Johannes AU - Roth J AD - Institute of Immunology, University of Munster, Munster, Germany. AD - Interdisciplinary Centre for Clinical Research, University of Munster, Munster, Germany; and. FAU - Vogl, Thomas AU - Vogl T AD - Institute of Immunology, University of Munster, Munster, Germany. AD - Interdisciplinary Centre for Clinical Research, University of Munster, Munster, Germany; and. FAU - Viemann, Dorothee AU - Viemann D AD - Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany; viemann.dorothee@mh-hannover.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20161219 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Alarmins) RN - 0 (Calgranulin A) RN - 0 (Calgranulin B) RN - 0 (Lipopolysaccharide Receptors) RN - 0 (Sialic Acid Binding Ig-like Lectin 3) SB - IM MH - Alarmins/*blood MH - Animals MH - Calgranulin A/*blood/therapeutic use MH - Calgranulin B/*blood/therapeutic use MH - Cells, Cultured MH - Female MH - Humans MH - Infant, Newborn MH - Lipopolysaccharide Receptors/genetics/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Monocytes/*immunology MH - Neonatal Sepsis/*blood/prevention & control MH - Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism OTO - NOTNLM OT - MDSC OT - calprotectin OT - myeloid cells OT - newborn OT - sepsis EDAT- 2016/12/21 06:00 MHDA- 2017/09/07 06:00 CRDT- 2016/12/21 06:00 PHST- 2016/09/24 00:00 [received] PHST- 2016/11/28 00:00 [accepted] PHST- 2016/12/21 06:00 [pubmed] PHST- 2017/09/07 06:00 [medline] PHST- 2016/12/21 06:00 [entrez] AID - fj.201601083R [pii] AID - 10.1096/fj.201601083R [doi] PST - ppublish SO - FASEB J. 2017 Mar;31(3):1153-1164. doi: 10.1096/fj.201601083R. Epub 2016 Dec 19.