In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock
| Autor: | Johannes Roth, Judith Friesenhagen, Thomas Vogl, Beate Fehlhaber, Constantin von Kaisenberg, Thomas Ulas, Johanna Burgmann, Marco Ginzel, Mandy Busse, Lara Mellinger, Dorothee Viemann, Anna S. Heinemann, Sabine Pirr, Maren von Köckritz-Blickwede |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine CD14 Sialic Acid Binding Ig-like Lectin 3 Population Lipopolysaccharide Receptors Biochemistry Monocytes Sepsis Mice 03 medical and health sciences Immune system Genetics medicine Alarmins Animals Calgranulin B Humans Calgranulin A education Molecular Biology Cells Cultured education.field_of_study biology business.industry Septic shock Infant Newborn medicine.disease Mice Inbred C57BL 030104 developmental biology Integrin alpha M Cord blood Immunology biology.protein Female Neonatal Sepsis Calprotectin business Biotechnology |
| Zdroj: | The FASEB Journal. 31:1153-1164 |
| ISSN: | 1530-6860 0892-6638 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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