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Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production

Nature Medicine volume 15, pages 42–49 (2009)Cite this article

A Corrigendum to this article was published on 01 April 2009

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Abstract

Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs—also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-α) reprogram macrophages by releasing prostaglandin E2 that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups.

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Figure 1: Effect of intravenous injection of BMSCs on the course of sepsis after CLP.
Figure 2: Fate of injected BMSCs and effect of BMSC treatment on survival of normal and immune cell–depleted mice.
Figure 3: Effect of BMSC treatment on leukocyte trafficking.
Figure 4: Characterization of control and stimulated mononuclear cells in CLP mice in vivo and in vitro.
Figure 5: Studies of molecular alterations underlying the effect of BMSCs on macrophages.
Figure 6: Summary of studies of the molecular pathways involved in the interaction between BMSC and macrophages.

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  • 06 April 2009

    In the version of this article initially published, the labeling in (Figure 4) was incorrect. In panel (b), the cells in the left two FACS plots are shown based on their size (FSC, y axis) and CD11b expression (x axis), and the cells in the right two FACS plots are shown based on their F4/80 expression (y axis) and GR1 expression (x axis). In panel (c), the curves should start at 1 h. In panel (d), the text labeling the y axis should read “in vitro,” not “in vivo.” The errors have been corrected in the HTML and PDF versions of this article.

References

  1. Ulloa, L. & Tracey, K.J. The “cytokine profile”: a code for sepsis. Trends Mol. Med. 11, 56–63 (2005).

    Article  CAS  Google Scholar 

  2. Le Blanc, K. et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363, 1439–1441 (2004).

    Article  Google Scholar 

  3. Noel, D., Djouad, F., Bouffi, C., Mrugala, D. & Jorgensen, C. Multipotent mesenchymal stromal cells and immune tolerance. Leuk. Lymphoma 48, 1283–1289 (2007).

    Article  CAS  Google Scholar 

  4. Rasmusson, I. Immune modulation by mesenchymal stem cells. Exp. Cell Res. 312, 2169–2179 (2006).

    Article  CAS  Google Scholar 

  5. Ringden, O. et al. Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 21, 2271–2276 (2007).

    Article  CAS  Google Scholar 

  6. Bochud, P.Y. & Calandra, T. Pathogenesis of sepsis: new concepts and implications for future treatment. BMJ 326, 262–266 (2003).

    Article  CAS  Google Scholar 

  7. Calandra, T. Pathogenesis of septic shock: implications for prevention and treatment. J. Chemother. 13 (Spec. No. 1), 173–180 (2001).

    Article  CAS  Google Scholar 

  8. Hubbard, W.J. et al. Cecal ligation and puncture. Shock 24 Suppl 1, 52–57 (2005).

    Article  Google Scholar 

  9. Togel, F. et al. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am. J. Physiol. Renal. Physiol. 292, F1626–F1635 (2007).

    Article  CAS  Google Scholar 

  10. Togel, F. et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am. J. Physiol. Renal Physiol. 289, F31–F42 (2005).

    Article  Google Scholar 

  11. Semedo, P. et al. Mesenchymal stem cells ameliorate tissue damages triggered by renal ischemia and reperfusion injury. Transplant. Proc. 39, 421–423 (2007).

    Article  CAS  Google Scholar 

  12. Lange, C. et al. Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int. 68, 1613–1617 (2005).

    Article  Google Scholar 

  13. Shinkai, Y. et al. RAG-2–deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).

    Article  CAS  Google Scholar 

  14. Habu, S. et al. In vivo effects of anti-asialo GM1. I. Reduction of NK activity and enhancement of transplanted tumor growth in nude mice. J. Immunol. 127, 34–38 (1981).

    CAS  PubMed  Google Scholar 

  15. Kasai, M. et al. In vivo effect of anti-asialo GM1 antibody on natural killer activity. Nature 291, 334–335 (1981).

    Article  CAS  Google Scholar 

  16. van Rooijen, N., Sanders, A. & van den Berg, T.K. Apoptosis of macrophages induced by liposome-mediated intracellular delivery of clodronate and propamidine. J. Immunol. Methods 193, 93–99 (1996).

    Article  CAS  Google Scholar 

  17. Moore, K.W., O'Garra, A., de Waal Malefyt, R., Vieira, P. & Mosmann, T.R. Interleukin-10. Annu. Rev. Immunol. 11, 165–190 (1993).

    Article  CAS  Google Scholar 

  18. Wang, J., Wakeham, J., Harkness, R. & Xing, Z. Macrophages are a significant source of type 1 cytokines during mycobacterial infection. J. Clin. Invest. 103, 1023–1029 (1999).

    Article  CAS  Google Scholar 

  19. Bonder, C.S. et al. P-selectin can support both TH1 and TH2 lymphocyte rolling in the intestinal microvasculature. Am. J. Pathol. 167, 1647–1660 (2005).

    Article  CAS  Google Scholar 

  20. Perretti, M., Szabo, C. & Thiemermann, C. Effect of interleukin-4 and interleukin-10 on leucocyte migration and nitric oxide production in the mouse. Br. J. Pharmacol. 116, 2251–2257 (1995).

    Article  CAS  Google Scholar 

  21. Cassatella, M.A. The neutrophil: one of the cellular targets of interleukin-10. Int. J. Clin. Lab. Res. 28, 148–161 (1998).

    Article  CAS  Google Scholar 

  22. Ajuebor, M.N. et al. Role of resident peritoneal macrophages and mast cells in chemokine production and neutrophil migration in acute inflammation: evidence for an inhibitory loop involving endogenous IL-10. J. Immunol. 162, 1685–1691 (1999).

    CAS  PubMed  Google Scholar 

  23. Hernandez, L.A. et al. Role of neutrophils in ischemia-reperfusion–induced microvascular injury. Am. J. Physiol. 253, H699–H703 (1987).

    CAS  PubMed  Google Scholar 

  24. Jaeschke, H. & Smith, C.W. Mechanisms of neutrophil-induced parenchymal cell injury. J. Leukoc. Biol. 61, 647–653 (1997).

    Article  CAS  Google Scholar 

  25. Nussler, A.K., Wittel, U.A., Nussler, N.C. & Beger, H.G. Leukocytes, the Janus cells in inflammatory disease. Langenbecks Arch. Surg. 384, 222–232 (1999).

    Article  CAS  Google Scholar 

  26. Matthijsen, R.A. et al. Myeloperoxidase is critically involved in the induction of organ damage after renal ischemia reperfusion. Am. J. Pathol. 171, 1743–1752 (2007).

    Article  CAS  Google Scholar 

  27. Jung, Y.J., Isaacs, J.S., Lee, S., Trepel, J. & Neckers, L. IL-1beta-mediated up-regulation of HIF-1α via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis. FASEB J. 17, 2115–2117 (2003).

    Article  CAS  Google Scholar 

  28. Nakao, S. et al. Tumor necrosis factor α (TNF-α)-induced prostaglandin E2 release is mediated by the activation of cyclooxygenase-2 (COX-2) transcription via NFκB in human gingival fibroblasts. Mol. Cell. Biochem. 238, 11–18 (2002).

    Article  CAS  Google Scholar 

  29. Ramsay, R.G., Ciznadija, D., Vanevski, M. & Mantamadiotis, T. Transcriptional regulation of cyclo-oxygenase expression: three pillars of control. Int. J. Immunopathol. Pharmacol. 16, 59–67 (2003).

    CAS  PubMed  Google Scholar 

  30. Aggarwal, S. & Pittenger, M.F. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105, 1815–1822 (2005).

    Article  CAS  Google Scholar 

  31. Sotiropoulou, P.A., Perez, S.A., Gritzapis, A.D., Baxevanis, C.N. & Papamichail, M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24, 74–85 (2006).

    Article  Google Scholar 

  32. Pevsner-Fischer, M. et al. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood 109, 1422–1432 (2007).

    Article  CAS  Google Scholar 

  33. Crisostomo, P.R. et al. Gender differences in injury induced mesenchymal stem cell apoptosis and VEGF, TNF, IL-6 expression: role of the 55 kDa TNF receptor (TNFR1). J. Mol. Cell. Cardiol. 42, 142–149 (2007).

    Article  CAS  Google Scholar 

  34. Park, Y.K. et al. Nitric oxide donor, (+/−)-S-nitroso-N-acetylpenicillamine, stabilizes transactive hypoxia-inducible factor-1α by inhibiting von Hippel-Lindau recruitment and asparagine hydroxylation. Mol. Pharmacol. 74, 236–245 (2008).

    Article  CAS  Google Scholar 

  35. Bal-Price, A., Gartlon, J. & Brown, G.C. Nitric oxide stimulates PC12 cell proliferation via cGMP and inhibits at higher concentrations mainly via energy depletion. Nitric Oxide 14, 238–246 (2006).

    Article  CAS  Google Scholar 

  36. Bianco, P., Riminucci, M., Gronthos, S. & Robey, P.G. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19, 180–192 (2001).

    Article  CAS  Google Scholar 

  37. Chamberlain, G., Fox, J., Ashton, B. & Middleton, J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25, 2739–2749 (2007).

    Article  CAS  Google Scholar 

  38. Mansilla, E. et al. Human mesenchymal stem cells are tolerized by mice and improve skin and spinal cord injuries. Transplant. Proc. 37, 292–294 (2005).

    Article  CAS  Google Scholar 

  39. van Laar, J.M. & Tyndall, A. Adult stem cells in the treatment of autoimmune diseases. Rheumatology (Oxford) 45, 1187–1193 (2006).

    Article  CAS  Google Scholar 

  40. Corcione, A. et al. Human mesenchymal stem cells modulate B-cell functions. Blood 107, 367–372 (2006).

    Article  CAS  Google Scholar 

  41. Kubo, S. et al. E-prostanoid (EP)2/EP4 receptor-dependent maturation of human monocyte-derived dendritic cells and induction of helper T2 polarization. J. Pharmacol. Exp. Ther. 309, 1213–1220 (2004).

    Article  CAS  Google Scholar 

  42. Shinomiya, S. et al. Regulation of TNFα and interleukin-10 production by prostaglandins I2 and E2: studies with prostaglandin receptor–deficient mice and prostaglandin E-receptor subtype-selective synthetic agonists. Biochem. Pharmacol. 61, 1153–1160 (2001).

    Article  CAS  Google Scholar 

  43. Hata, A.N. & Breyer, R.M. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol. Ther. 103, 147–166 (2004).

    Article  CAS  Google Scholar 

  44. Le Blanc, K. et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371, 1579–1586 (2008).

    Article  CAS  Google Scholar 

  45. Miyaji, T. et al. Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice. Kidney Int. 64, 1620–1631 (2003).

    Article  CAS  Google Scholar 

  46. Yasuda, H., Yuen, P.S., Hu, X., Zhou, H. & Star, R.A. Simvastatin improves sepsis-induced mortality and acute kidney injury via renal vascular effects. Kidney Int. 69, 1535–1542 (2006).

    Article  CAS  Google Scholar 

  47. Imai, Y., Ibata, I., Ito, D., Ohsawa, K. & Kohsaka, S. A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem. Biophys. Res. Commun. 224, 855–862 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank M.J. Brownstein for continuous advice and discussions; J. M. Weiss (NCI, NIH) for supplying the Ifng−/− mice; A. Keane-Myers (NIAID) for supplying the Il10−/− mice; Christophe Cataisson (NCI) for supplying the Tnfrsf1a−/− and Tnfrsf1b−/− mice; T. Merkel (US Food and Drug Administration) for supplying the Tlr4−/− and Myd88−/− mice; K. Holmbeck and L. Szabova (NIDCR) for the FVB/NJ mouse cells; and I. Szalayova and S. Key (NIDCR) for their superb technical help. The research was supported by the intramural programs of the NIDCR and the NIDDK, NIH.

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Author notes

  1. Krisztián Németh, Asada Leelahavanichkul, Robert A Star and Éva Mezey: These authors contributed equally to this work.

Authors and Affiliations

  1. National Institute of Dental and Craniofacial Research (NIDCR), Craniofacial and Skeletal Diseases Branch, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Krisztián Németh, Balázs Mayer, Alissa Parmelee, Pamela G Robey, Kantima Leelahavanichkul & Éva Mezey

  2. National Institute of Diabetes and Digestive Kidney Diseases (NIDDK), Renal Diagnostics and Therapeutics Unit, 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Asada Leelahavanichkul, Peter S T Yuen, Kent Doi, Xuzhen Hu & Robert A Star

  3. National Cancer Institute (NCI), Experimental Immunology Branch, US National Institutes of Health (NIH), 9000 Rockville Pike, Bethesda, 20892, Maryland, USA

    Ivett Jelinek

  4. Department of Genetics, University of North Carolina, 4341 Medical Biomolecular Research Building, Chapel Hill, 27599, North Carolina, USA

    Beverly H Koller

  5. Department of Pharmacology and Toxicology, East Carolina University, Greenville, 27858, North Carolina, USA

    Jared M Brown

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Contributions

K.N., A.L., P.S.T.Y., R.A.S. and E.M. formulated the basic hypotheses and experimental design; K.N., A.L., E.M., P.S.T.Y. and R.A.S. collected and evaluated data on survival and organ injury; K.N. and A.L. performed the in vivo experiments; A.L., P.S.T.Y., A.P., K.D., K.L. and X.H. assisted in the in vivo experiments and histology; P.G.R. consulted on BMSC biology; K.N. formulated the molecular mechanism hypothesis and designed and performed in vitro and ex vivo assays; B.H.K. helped to test the involvement of the prostaglandin receptors; J.M.B. and B.M. contributed to testing the involvement of COX2; B.M. performed the measurements for tissue peroxidase; I.J. performed FACS experiments; E.M. wrote the initial manuscript and prepared the figures; all of the authors edited the manuscript.

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Correspondence to Éva Mezey.

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Németh, K., Leelahavanichkul, A., Yuen, P. et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15, 42–49 (2009). https://doi.org/10.1038/nm.1905

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