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

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-) reprogram macrophages by releasing prostaglandin E 2 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. © 2008 Nature Publishing GroupCorrespondence should be addressed to E.M. (E-mail: mezeye@mail.nih.gov).. 6 These authors contributed equally to this work. AUTHOR 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.Note: Supplementary information is available on the Nature Medicine website. In the last few years, it has been discovered that BMSCs are potent modulators of immune responses 2-5 . We wondered whether such cells could bring the immune response back into balance, thus attenuating the underlying pathophysiology that eventually leads to severe sepsis, septic shock and death 6,7 . NIH Public AccessAs a model of sepsis, we chose cecal ligation and puncture (CLP), a procedure that has been used for more than two decades 8 . This mouse model closely resembles the human disease: it has a focal origin (cecum), is caused by multiple intestinal organisms, and results in septicemia with release of bacterial toxins into the circulation. With no treatment, the ma...

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…MSCs also seem to attenuate end-organ infl ammatory damage. 40 Intravenous MSCs improve lung histology and decrease concentrations of proinfl ammatory cytokines in BAL fl uid after infection, 28,38 decrease concentrations of infl ammatory cytokines in cardiac tissue and improve cardiac function after intravenous LPS, 36 and also lower renal expression of proinfl ammatory cytokines and improve serological markers of kidney function after caecal ligation and puncture. 37 These eff ects occurred without substantial MSC localisation to the studied tissue, which suggests a paracrine mechanism.…”

“…39 MSCs might also have a therapeutic benefi t in sepsis through reprogramming of host macrophages. In a series of well designed in-vivo experiments, Németh and colleagues 40 reported a therapeutic pathway in which MSCs exposed to TNFα or LPS increase production of prostaglandin E2 (PGE2). This pathway drives resident macrophages towards the M2 antiinfl ammatory phenotype, thereby increasing their production of the anti-infl ammatory cytokine interleukin 10 and causing decreased infl ammation and infl ammatory infi ltration into tissue.…”

Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis

“…1,2 MSC-based therapies have provided convincing evidence for their potential antiinflammatory and immunomodulatory effects in treating a variety of inflammatory and autoimmune diseases, including ulcerative colitis (UC), 3 rheumatoid arthritis 4 and sepsis. 5 MSCs can migrate to sites of tissue damage, 6,7 where they are activated by inflammatory cytokines (such as IFN-c) and several chemokines, which can recruit or suppress lymphocytes. [8][9][10][11] Interleukin-1b (IL-1b) is an important inflammatory factor that is expressed abundantly during the active phase of UC.…”

Is Immunomodulation a Principal Mechanism Underlying How Cell-Based Therapies Enhance Stroke Recovery?

“…Similarly, as described below, cells entrapped in the spleen could modify splenocytes to exert anti-inflammatory properties by producing interleukin (IL)-4 and IL-10 ( Fig. 2) [51,52]. The systemic administration of autologous bone marrow mononuclear cells has also been found to reduce the levels of proinflammatory molecules, while increasing antiinflammatory cytokines within the brain and blood [54,55].…”

“…For example, MSCs lodging in the lungs may reprogram alveolar macrophages to release anti-inflammatory cytokines through cell-to-cell contact (Fig. 2) [52]. Increasing evidence suggests that MSCs may modulate the immune response after stroke.…”