Bone marrow stromal cells attenuate sepsis via prostaglandin E2 dependent reprogramming of host macrophages to increase their interleukin 10 production
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 a) 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.
Nature Medicine