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Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation

Abstract

Myeloid-derived suppressor cells (MDSCs) are pathologically activated and relatively immature myeloid cells that have been implicated in the immunological regulation of many pathologic conditions1,2. Phenotypically and morphologically, MDSCs are similar to neutrophils (PMN-MDSCs) and monocytes (M-MDSCs). However, they have potent suppressive activity and distinct gene expression profiles and biochemical characteristics3. No or very few MDSCs are observed in steady-state physiological conditions. Therefore, until recently, accumulation of MDSCs was considered a consequence of pathological processes or pregnancy. Here, we report that MDSCs with a potent ability to suppress T cells are present during the first weeks of life in mice and humans. MDSC suppressive activity was triggered by lactoferrin and mediated by nitric oxide, PGE2, and S100A9 and S100A8 proteins. MDSCs from newborns had a transcriptome similar to that of tumor MDSCs, but with strong upregulation of an antimicrobial gene network, and had potent antibacterial activity. MDSCs played a critical role in control of experimental necrotizing enterocolitis (NEC) in newborn mice. MDSCs in infants with very low weight, who are prone to NEC, had lower MDSC levels and suppressive activity than did infants with normal weight. Thus, the transitory presence of MDSCs may be critical for regulation of inflammation in newborns.

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Figure 1: Expansion of MDSCs in NBM.
Figure 2: Lactoferrin is responsible for accumulation of MDSCs in NBM.
Figure 3: MDSCs in human infants.
Figure 4: Role of MDSCs in a necrotizing enterocolitis (NEC) experimental model.

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References

  1. Marvel, D. & Gabrilovich, D.I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Invest. 125, 3356–3364 (2015).

    Article  Google Scholar 

  2. Gabrilovich, D.I. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5, 3–8 (2017).

    Article  CAS  Google Scholar 

  3. Bronte, V. et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 7, 12150 (2016).

    Article  CAS  Google Scholar 

  4. Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nat. Immunol. https://doi.org/10.1038/s41590-017-0022-x 2018).

    Article  CAS  Google Scholar 

  5. Obermajer, N. et al. PGE2-driven induction and maintenance of cancer-associated myeloid-derived suppressor cells. Immunol. Invest. 41, 635–657 (2012).

    Article  CAS  Google Scholar 

  6. Nagaraj, S. et al. Antigen-specific CD4+ T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling. Cancer Res. 72, 928–938 (2012).

    Article  CAS  Google Scholar 

  7. Youn, J.I., Collazo, M., Shalova, I.N., Biswas, S.K. & Gabrilovich, D.I. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 91, 167–181 (2012).

    Article  CAS  Google Scholar 

  8. Manitz, M.P. et al. Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants in vitro. Mol. Cell. Biol. 23, 1034–1043 (2003).

    Article  CAS  Google Scholar 

  9. Park, J.Y., Pillinger, M.H. & Abramson, S.B. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin. Immunol. 119, 229–240 (2006).

    Article  CAS  Google Scholar 

  10. Deshmukh, H.S. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat. Med. 20, 524–530 (2014).

    Article  CAS  Google Scholar 

  11. Vogel, H.J. Lactoferrin, a bird's eye view. Biochem. Cell Biol. 90, 233–244 (2012).

    Article  CAS  Google Scholar 

  12. Warner, B.B. & Tarr, P.I. Necrotizing enterocolitis and preterm infant gut bacteria. Semin. Fetal Neonatal Med. 21, 394–399 (2016).

    Article  Google Scholar 

  13. Denning, T.L., Bhatia, A.M., Kane, A.F., Patel, R.M. & Denning, P.L. Pathogenesis of NEC: role of the innate and adaptive immune response. Semin. Perinatol. 41, 15–28 (2017).

    Article  Google Scholar 

  14. Condamine, T. et al. Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci. Immunol. 1, aaf8943 (2016).

    Article  Google Scholar 

  15. Niño, D.F., Sodhi, C.P. & Hackam, D.J. Necrotizing enterocolitis: new insights into pathogenesis and mechanisms. Nat. Rev. Gastroenterol. Hepatol. 13, 590–600 (2016).

    Article  Google Scholar 

  16. Condamine, T. et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J. Clin. Invest. 124, 2626–2639 (2014).

    Article  CAS  Google Scholar 

  17. James, B.R. et al. CpG-mediated modulation of MDSC contributes to the efficacy of Ad5-TRAIL therapy against renal cell carcinoma. Cancer Immunol. Immunother. 63, 1213–1227 (2014).

    Article  CAS  Google Scholar 

  18. Dominguez, G.A. et al. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin. Cancer Res. 23, 2942–2950 (2017).

    Article  CAS  Google Scholar 

  19. Egan, C.E. et al. Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. J. Clin. Invest. 126, 495–508 (2016).

    Article  Google Scholar 

  20. Gervassi, A. et al. Myeloid derived suppressor cells are present at high frequency in neonates and suppress in vitro T cell responses. PLoS One 9, e107816 (2014).

    Article  Google Scholar 

  21. Curran, C.S. & Bertics, P.J. Lactoferrin regulates an axis involving CD11b and CD49d integrins and the chemokines MIP-1alpha and MCP-1 in GM-CSF-treated human primary eosinophils. J. Interferon Cytokine Res. 32, 450–461 (2012).

    Article  CAS  Google Scholar 

  22. Cheng, P. et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J. Exp. Med. 205, 2235–2249 (2008).

    Article  CAS  Google Scholar 

  23. Heinemann, A.S. et al. In neonates S100A8/S100A9 alarmins prevent the expansion of a specific inflammatory monocyte population promoting septic shock. FASEB J. 31, 1153–1164 (2017).

    Article  CAS  Google Scholar 

  24. Sinha, P. et al. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J. Immunol. 181, 4666–4675 (2008).

    Article  CAS  Google Scholar 

  25. St-Onge, M. et al. Characterization of prostaglandin E2 generation through the cyclooxygenase (COX)-2 pathway in human neutrophils. Biochim. Biophys. Acta 1771, 1235–1245 (2007).

    Article  CAS  Google Scholar 

  26. Wehbi, V.L. & Taskén, K. Molecular mechanisms for cAMP-mediated immunoregulation in t cells: role of anchored protein kinase A signaling units. Front. Immunol. 7, 222 (2016).

    Article  Google Scholar 

  27. Talukder, J.R., Griffin, A., Jaima, A., Boyd, B. & Wright, J. Lactoferrin ameliorates prostaglandin E2-mediated inhibition of Na+-glucose cotransport in enterocytes. Can. J. Physiol. Pharmacol. 92, 9–20 (2014).

    Article  CAS  Google Scholar 

  28. Trentini, A. et al. Vaginal lactoferrin modulates PGE2, MMP-9, MMP-2, and TIMP-1 amniotic fluid concentrations. Mediators Inflamm. 2016, 3648719 (2016).

    Article  Google Scholar 

  29. Rasheed, N., Alghasham, A. & Rasheed, Z. Lactoferrin from Camelus dromedarius inhibits nuclear transcription factor-kappa B activation, cyclooxygenase-2 expression and prostaglandin E2 production in stimulated human chondrocytes. Pharmacognosy Res. 8, 135–141 (2016).

    Article  CAS  Google Scholar 

  30. Li, B. & Dewey, C.N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics 12, 323 (2011).

    Article  CAS  Google Scholar 

  31. Love, M.I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article  Google Scholar 

  32. Mosconi, E. et al. Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development. Mucosal Immunol. 3, 461–474 (2010).

    Article  CAS  Google Scholar 

  33. Tian, R. et al. Characterization of a necrotizing enterocolitis model in newborn mice. Int. J. Clin. Exp. Med. 3, 293–302 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Rager, T.M., Olson, J.K., Zhou, Y., Wang, Y. & Besner, G.E. Exosomes secreted from bone marrow-derived mesenchymal stem cells protect the intestines from experimental necrotizing enterocolitis. J. Pediatr. Surg. 51, 942–947 (2016).

    Article  Google Scholar 

  35. Kubinak J.L. et al.MyD88 signaling in T cells directs IgA-mediated control of the microbiota to promote health. Cell Host Microbe 17, 153–163 (2015).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Wistar Institute Animal and Bioinformatics core facilities as well as NIH grant CA165065 to D.I.G. and V.K. The work was also supported by the Recruitment Program for Foreign Experts (Thousand Talents Plan, WQ2014440O204), the Start-up Fund for High-level Talents of Sun Yat-sen University, and the Leading Talents of Guangdong Province Program (D.I.G.). This work was supported by the following grants to J.Z.: the Introduction of Innovative R&D Team Program of Guangdong Province (2009010058), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (GDUPS, 2014), the National Natural Science Foundation of China (91542112; 81571520, 81771665, and 81742002), and the Provincial Talents Cultivated by the 'Thousand-Hundred-Ten' Program of Guangdong Province, 111 Project (B12003). We thank S. Grey-Owen (University of Toronto) and O.M. Conneely (Baylor College of Medicine) for providing LF-KO mice and T. Vogl and J. Roth (Institute of Immunology, Muenster) for providing S100A9-KO mice. We thank Y. Yu (Tianjin Medical University) for providing Cox-2-KO mice and H. Zhang (Sun Yat-sen University) for providing OT-1 transgenic mice.

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Conceptualization, D.I.G. and J.Z.; formal analysis, A.V.K.; investigation, Y.-M.H., X.L., M.P., Y.-F.L., S.-Y.F., Q.-J.Y., Y.-H.Z., and L.W.; resources, Y.N. and E.A.J.; writing original draft, D.I.G. and J.Z.; manuscript review and editing, D.I.G., J.Z., Y.N., and V.K.; supervision, D.I.G. and J.Z.; funding acquisition, D.I.G., J.Z., and V.K.

Corresponding authors

Correspondence to Dmitry I Gabrilovich or Jie Zhou.

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The authors declare no competing financial interests.

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He, YM., Li, X., Perego, M. et al. Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation. Nat Med 24, 224–231 (2018). https://doi.org/10.1038/nm.4467

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