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      In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock.

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          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-/Ly6Chi 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-1int/Ly6G-/Ly6Chi 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 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.

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          Author and article information

          Journal
          FASEB J.
          FASEB journal : official publication of the Federation of American Societies for Experimental Biology
          FASEB
          1530-6860
          0892-6638
          March 2017
          : 31
          : 3
          Affiliations
          [1 ] Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany.
          [2 ] Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
          [3 ] Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany.
          [4 ] Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
          [5 ] Department of Gynecology and Prenatal Medicine, Hannover Medical School, Hannover, Germany.
          [6 ] Institute of Immunology, University of Münster, Münster, Germany.
          [7 ] Interdisciplinary Centre for Clinical Research, University of Münster, Münster, Germany; and.
          [8 ] Department of Pediatric Pneumology, Allergy, and Neonatology, Hannover Medical School, Hannover, Germany; viemann.dorothee@mh-hannover.de.
          Article
          fj.201601083R
          10.1096/fj.201601083R
          27993995
          3f1b9451-826b-4041-8965-5dd231af329f
          History

          MDSC,calprotectin,myeloid cells,newborn,sepsis
          MDSC, calprotectin, myeloid cells, newborn, sepsis

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