Bone marrow stromal cells attenuate sepsis via prostaglandin E2— dependent reprogramming of host macrophages to increase their interleukin-10 production
Nemeth, Krisztian; Leelahavanichkul, Asada; Yuen, Peter S. T.; Mayer, Balazs; Parmelee, Alissa; Doi, Kent; Robey, Pamela G.; Leelahavanichkul, Kantima; Koller, Beverly H.; Brown, Jared M.; Hu, Xuzhen; Jelinek, Ivett; Star, Robert A.; Mezey, Eva
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.Sepsis, a serious medical condition that affects 18 million people per year worldwide, is characterized by a generalized inflammatory state caused by infection. Widespread activation of inflammation and coagulation pathways progresses to multiple organ dysfunction, collapse of the circulatory system (septic shock) and death. Because as many people die of sepsis annually as from acute myocardial infarction1, a new treatment regimen is desperately needed. In the last few years, it has been discovered that BMSCs are potent modulators of immune responses2-5. 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 death6,7. As a model of sepsis, we chose cecal ligation and puncture (CLP), a procedure that has been used for more than two decades8. 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 majority of the mice die 24-48 h postoperatively. Originally published Nature Medicine, Vol. 15, No. 1, Jan 2009
Nemeth, Krisztian, & Leelahavanichkul, Asada, & Yuen, Peter S. T., & Mayer, Balazs, & Parmelee, Alissa, & Doi, Kent, & Robey, Pamela G., & Leelahavanichkul, Kantima, & Koller, Beverly H., & Brown, Jared M., & Hu, Xuzhen, & Jelinek, Ivett, & Star, Robert A., & Mezey, Eva. (January 2009). Bone marrow stromal cells attenuate sepsis via prostaglandin E2— dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine, 15(1), 42- 49. Retrieved from http://hdl.handle.net/10342/3364
Nemeth, Krisztian, and Leelahavanichkul, Asada, and Yuen, Peter S. T., and Mayer, Balazs, and Parmelee, Alissa, and Doi, Kent, and Robey, Pamela G., and Leelahavanichkul, Kantima, and Koller, Beverly H., and Brown, Jared M., and Hu, Xuzhen, and Jelinek, Ivett, and Star, Robert A., and Mezey, Eva. "Bone marrow stromal cells attenuate sepsis via prostaglandin E2— dependent reprogramming of host macrophages to increase their interleukin-10 production". Nature Medicine. 15:1. (42-49), January 2009. April 26, 2019. http://hdl.handle.net/10342/3364.
Nemeth, Krisztian and Leelahavanichkul, Asada and Yuen, Peter S. T. and Mayer, Balazs and Parmelee, Alissa and Doi, Kent and Robey, Pamela G. and Leelahavanichkul, Kantima and Koller, Beverly H. and Brown, Jared M. and Hu, Xuzhen and Jelinek, Ivett and Star, Robert A. and Mezey, Eva, "Bone marrow stromal cells attenuate sepsis via prostaglandin E2— dependent reprogramming of host macrophages to increase their interleukin-10 production," Nature Medicine 15, no. 1 (January 2009), http://hdl.handle.net/10342/3364 (accessed April 26, 2019).
Nemeth, Krisztian, Leelahavanichkul, Asada, Yuen, Peter S. T., Mayer, Balazs, Parmelee, Alissa, Doi, Kent, Robey, Pamela G., Leelahavanichkul, Kantima, Koller, Beverly H., Brown, Jared M., Hu, Xuzhen, Jelinek, Ivett, Star, Robert A., Mezey, Eva. Bone marrow stromal cells attenuate sepsis via prostaglandin E2— dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine. January 2009; 15(1): 42-49. http://hdl.handle.net/10342/3364. Accessed April 26, 2019.
East Carolina University