Sci. Signal., 13 January 2009
Sepsis Changing the Program
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
Sepsis is a potentially fatal condition that is characterized by a massive, systemic inflammatory response to infection in the blood. Mesenchymal stem cells (MSCs) have been successfully used to modulate various immune responses (see Tyndall and Pistoia), which led Németh et al. to investigate whether bone marrow (BM)–derived MSCs [BM stromal cells (BMSCs)] might be useful in the treatment of sepsis. They performed their experiments in mice that had undergone cecal ligation and puncture (CLP), a surgical procedure that resulted in the infiltration of intestinal microbes into the blood. Mice that received BMSCs intravenously at the time of CLP survived better than did mice that underwent CLP without BMSCs. BMSC-treated mice had a lower abundance of proinflammatory cytokines in their serum than did untreated mice and had a higher concentration of the antiinflammatory cytokine interleukin-10 (IL-10). Depletion of macrophages abolished the therapeutic effects of BMSCs, as did blockade of IL-10 signaling. Macrophages cultured in direct contact with BMSCs in the presence of lipopolysaccharide (LPS) secreted more IL-10 than did macrophages separated from BMSCs by a membrane. IL-10 production by macrophages was dependent on intact Toll-like receptor 4 (TLR4) signaling and cyclooxygenase activity in the BMSCs. Finally, the authors showed that LPS triggered BMSCs to produce prostaglandin E2 (PGE2), which stimulated macrophages through two isoforms of the PGE2 receptor to increase their secretion of IL-10. Together, these data suggest that BMSCs might be an effective therapy against sepsis in humans.
K. Németh, A. Leelahavanichkul, P. S. T. Yuen, B. Mayer, A. Parmelee, K. Doi, P. G. Robey, K. Leelahavanichkul, B. H. Koller, J. M. Brown, X. Hu, I. Jelinek, R. A. Star, E. Mezey, 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). [PubMed]
A. Tyndall, V. Pistoia, Mesenchymal stem cells combat sepsis. Nat. Med. 15, 18–20 (2009). [PubMed]
Citation: J. F. Foley, Changing the Program. Sci. Signal. 2, ec11 (2009).
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