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

Nature Immunology volume 18, pages 622–632 (2017)Cite this article

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A Corrigendum to this article was published on 19 September 2017

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Abstract

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.

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Figure 1: LPS-induced transcriptomic changes in neonatal monocytes cause a shift from MyD88- to TRIF-dependent gene programs.
Figure 2: Inverse basal programming causes the reciprocal use of MyD88- and TRIF-dependent signaling in neonatal and adult monocytes.
Figure 3: Neonatal monocytes differ from adult monocytes in their high basal activity of MyD88-dependent transcriptional activators refractory to LPS stimulation.
Figure 4: Perinatal S100 programming of MyD88- but not TRIF-dependent genes.
Figure 5: Human monocytes are postnatally reprogrammed by the gradual initiation of TRIF-dependent regulatory gene programs.
Figure 6: S100 alarmins prevent fatal sepsis in mouse neonates.
Figure 7: Cord blood levels of S100A8/A9 are inversely correlated with the risk of sepsis in human neonates.

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    In the version of this article initially published, the graphs in Figure 2e were incorrect. They have been replaced with the correct graphs. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank U. Nordhues and A. Weitz for excellent technical support. We thank W. Kolanus, S. Burgdorf, M. Beyer and A. Schlitzer for critical reading of the manuscript. ER-Hoxb8 was kindly provided by the laboratory of G. Haecker (University Hospital of Freiburg, Freiburg, Germany). This work was supported by the Interdisciplinary Center of Clinical Research at the University of Muenster (grants Vo2/004/14 and Ro2/003/15 to T.V. and J.R.), the Cluster of Excellence Cells in Motion (T.V., J.R. and K.B.-K.), the collaborative research centers 1009 and TRR34 of the German Research Foundation (grants B8 and B9 and grant C13, respectively, to T.V., J.R. and K.B.-K.), the Appenrodt Foundation (D.V.), the German Research Foundation (grant VI 538/6-1 to D.V.), the Volkswagen Foundation (D.V.) and the German Research Foundation (grants SFB 832, SFB 704 and INST 217/577-1 to J.L.S.). J.L.S. is a member of the Cluster of Excellence ImmunoSensation and an associated member of the German epigenome program DEEP.

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Author notes

  1. Thomas Ulas and Sabine Pirr: These authors contributed equally to this work.

Authors and Affiliations

  1. Genomics and Immunoregulation, LIMES-Institut, University of Bonn, Bonn, Germany

    Thomas Ulas & Joachim L Schultze

  2. Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany

    Sabine Pirr, Beate Fehlhaber, Marie S Bickes, Lara Mellinger, Anna S Heinemann, Johanna Burgmann, Jennifer Schöning, Sabine Schreek, Lena Völlger, Judith Friesenhagen & Dorothee Viemann

  3. Department of Physiological Chemistry and Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Hannover, Germany

    Torsten G Loof, Sandra Pfeifer, Friederike Reuner & Maren von Köckritz-Blickwede

  4. Institute of Immunology, University of Münster, Münster, Germany

    Thomas Vogl, Katarzyna Barczyk-Kahlert, Lena Fischer-Riepe, Stefanie Zenker & Johannes Roth

  5. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    Martin Stanulla

  6. Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany

    Shirin Glander

  7. Department of Gynaecology and Prenatal Medicine, Hannover Medical School, Hannover, Germany

    Constantin S von Kaisenberg

  8. Platform for Single Cell Genomics and Epigenomics at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany

    Joachim L Schultze

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Contributions

T.U., S. Pirr, M.v.K.-B., J.L.S., J.R. and D.V. conceived and designed the experiments. B.F., M.S.B., T.G.L., T.V., L.M., A.S.H., J.B., J.S., S.S., S. Pfeifer, F.R., L.V., M.v.K.-B., K.B.-K., J.F., L.F.-R. and S.Z. performed experiments. T.U., S. Pirr, M.S., S.G., K.B.-K., J.L.S., J.R. and D.V. analyzed the data. T.U., S. Pirr, C.S.v.K., J.L.S., J.R. and D.V. wrote the manuscript.

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Correspondence to Dorothee Viemann.

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Integrated supplementary information

Supplementary Figure 1 Experimental settings.

(a) Experimental setup and bioinformatic data analysis of transcriptomic changes induced in neonatal and adult monocytes by stimulation with 10 ng/ml LPS for 4h. QC/QA = quality control/quality assurance.

(b) Workflow for blood sampling from healthy infants (n = 127) and adults (n = 20).

(c) Timeline and workflow for S100a8/a9 pre-treatment and sepsis induction in S100a9−/− neonates.

Supplementary Figure 2 GOEA of LPS-induced changes in expression in human adult and neonatal monocytes.

Network visualization of GOEAs based on DE genes upon LPS treatment in adult (a) and neonatal (b) monocytes. Enriched GO-terms based on up-regulated DE genes are depicted by red nodes, based on down-regulated DE genes by blue borders. Color and size represent the corresponding FDR-adjusted enrichment P value (Q value). Overlap of genes between nodes is indicated by an edge.

Supplementary Figure 3 Hierarchical clustering (HC) and differences in protein expression between adult and neonatal monocytes.

(a-f) HC of genes enriched in the indicated GO clusters defined by GOEA of DE genes between the basal conditions. The z-scored log2 expression is displayed as heat map. (g) Extra- and intracellular flow cytometric analysis of protein expression of indicated MyD88- and TRIF-dependent genes in adult and neonatal monocytes 16h cultured with PBS (Ctrl) or LPS (each group n = 4). Bars represent means ± s.e.m. of mean fluorescence intensity (MFI). *P < 0.05, **P < 0.01, ***P < 0.0005 (unpaired t-test).

Supplementary Figure 4 Differences in MyD88- and TRIF-dependent gene expression between adult and neonatal mice.

(a) Relative basal gene expression of MyD88- and TRIF-dependent genes in murine adult and neonatal monocytes, determined by qRT-PCR. Bars represent means ± s.e.m. (n = 3). **P < 0.01, ***P < 0.005 (unpaired t-test). (b) LPS-induced fold changes (FC) of MyD88- and TRIF-dependent gene expression in murine adult and neonatal monocytes determined by qRT-PCR. Bars represent means ± s.e.m. (n = 3). *P < 0.05, **P < 0.01 (unpaired t-test.). (c) Plasma cytokine levels in adult and neonatal mice treated s.c. for 2h and 16h with 20 μg/g LPS or PBS (Ctrl). Bars represent means ± s.e.m. (adult: n = 8 (Ctrl), 6 (2h LPS) and 3 (16h LPS); neonatal: n = 6 (Ctrl), 4 (2h LPS) and 3 (16h LPS)). *P < 0.05, **P < 0.005, ***P < 0.0005 (unpaired t-test.).

Supplementary Figure 5 S100a9−/− neonates show a hyperinflammatory response to microbial challenges compared with wild-type neonates.

(a) Plasma cytokine levels in WT and S100a9−/− neonates 12h and 24h after infection with S. aureus. Bars represent means ± s.e.m (each group n = 5). *P < 0.05 (unpaired t-test). (b) Plasma cytokine levels in WT and S100a9−/− neonates 1.5h and 4h after s.c. injection of heat-inactivated S. aureus. Bars represent means ± s.e.m (each group n = 6 (1.5h), 5 (4h)). *P < 0.05, **P < 0.01 (unpaired t-test).

Supplementary Figure 6 S100A8/A9 induces inflammatory hyporesponsiveness and improves bacterial killing in human monocytes.

(a-c) Human adult and neonatal monocytes were isolated and cultured overnight in medium and, in case of adult monocytes, also in the presence of 10 μg/ml S100A8/A9 or 100 ng/ml S100A8 followed by challenges with PBS (Ctrl) or S. aureus (SA) (n = 4 in each group). Bars represent means ± s.e.m.. (a) IL-6 and TNF levels were determined in Ctrl and SA (1 MOI) supernatants 6h p.i.. * P < 0.05 (unpaired t-test). (b) Survival of SA in monocytes 3h (left panel) and 6h (right panel) after infection with 0.1 and 1.0 MOI SA. * P < 0.05, ** P < 0.01 (unpaired t-test). (c) Proportion of monocytes surviving 6h p.i. with 0.1 and 1.0 MOI SA. (d) Phagocytosis rate of adult and neonatal monocytes (each group n = 4) 30 min and 60 min after challenge with heat-killed SA. Bars represent means ± s.e.m..

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 2 and 4–7, and Supplementary Note 1 (PDF 2876 kb)

Supplementary Table 1

List of genes significantly differentially expressed after induction by LPS (PDF 783 kb)

Supplementary Table 3

List of genes differentially expressed between adult and neonatal monocytes at baseline (PDF 1344 kb)

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Ulas, T., Pirr, S., Fehlhaber, B. et al. S100-alarmin-induced innate immune programming protects newborn infants from sepsis. Nat Immunol 18, 622–632 (2017). https://doi.org/10.1038/ni.3745

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