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

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  • A Corrigendum to this article was published on 01 April 2009

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.

Change history

  • 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.

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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.

Author information

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.

Correspondence to Éva Mezey.

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Supplementary Figs. 1–5, Supplementary Table 1 and Suppmenentary Methods (PDF 1030 kb)

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