Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-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-alpha) 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.
Németh
Krisztián
K
National Institute of Dental and Craniofacial Research (NIDCR), Craniofacial and Skeletal Diseases Branch, NIH, Bethesda, MD 20892, USA.
Leelahavanichkul
Asada
A
Yuen
Peter S T
PS
Mayer
Balázs
B
Parmelee
Alissa
A
Doi
Kent
K
Robey
Pamela G
PG
Leelahavanichkul
Kantima
K
Koller
Beverly H
BH
Brown
Jared M
JM
Hu
Xuzhen
X
Jelinek
Ivett
I
Star
Robert A
RA
Mezey
Eva
E
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000502:physiology; D002429:Cecal Diseases / Q000150:complications / Q000401:mortality / Q000503:physiopathology / Q000628:therapy; D002432:Cecum / Q000293:injuries / Q000473:pathology; D065150:Cellular Reprogramming / Q000276:immunology / Q000502:physiology*; D015232:Dinoprostone / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000097:blood; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018805:Sepsis / Q000209:etiology / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D017154:Stromal Cells / Q000502:physiology / Q000637:transplantation; D016019:Survival Analysis; D014180:Transplantation; D014950:Wounds, Penetrating / Q000150:complications / Q000401:mortality / Q000503:physiopathology / Q000628:therapy
D016753:Interleukin-10; D015232:Dinoprostone