Serum miR-29a Is Upregulated in Acute Graft-versus-Host Disease and Activates Dendritic Cells through TLR Binding.
Acute graft-versus-host disease (aGVHD) continues to be a frequent and devastating complication of allogeneic hematopoietic stem cell transplantation (HSCT), posing as a significant barrier against the widespread use of HSCTs as a curative modality. Recent studies suggested serum/plasma microRNAs (miRs) may predict aGVHD onset. However, little is known about the functional role of circulating miRs in aGVHD. In this article, we show in two independent cohorts that miR-29a expression is significantly upregulated in the serum of allogeneic HSCT patients at aGVHD onset compared with non-aGVHD patients. Serum miR-29a is also elevated as early as 2 wk before time of diagnosis of aGVHD compared with time-matched control subjects. We demonstrate novel functional significance of serum miR-29a by showing that miR-29a binds and activates dendritic cells via TLR7 and TLR8, resulting in the activation of the NF-κB pathway and secretion of proinflammatory cytokines TNF-α and IL-6. Treatment with locked nucleic acid anti-miR-29a significantly improved survival in a mouse model of aGVHD while retaining graft-versus-leukemia effects, unveiling a novel therapeutic target in aGVHD treatment or prevention.
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Parvathi
P
Ranganathan
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Apollinaire
A
Ngankeu
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Nina C
0000-0001-9098-635X
NC
Zitzer
Department of Oncohematology, Bambino Gesù Children's Hospital, Rome 00165, Italy.
PierPaolo
0000-0002-1708-7291
P
Leoncini
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Xueyan
0000-0001-6441-5879
X
Yu
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210.
Lucia
L
Casadei
Department of Pediatrics, University of Southern California-Keck School of Medicine, Norris Comprehensive Cancer Center, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027.
Kishore
K
Challagundla
Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455; and.
Dawn K
DK
Reichenbach
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Sabrina
S
Garman
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Amy S
AS
Ruppert
Department of Anatomy, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.
Stefano
S
Volinia
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Jessica
J
Hofstetter
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Yvonne A
YA
Efebera
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
Steven M
SM
Devine
Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455; and.
Bruce R
BR
Blazar
Department of Pediatrics, University of Southern California-Keck School of Medicine, Norris Comprehensive Cancer Center, Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, CA 90027.
Muller
M
Fabbri
Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; ramiro.garzon@osumc.edu.
Ramiro
R
Garzon
D000208:Acute Disease; D015331:Cohort Studies; D003713:Dendritic Cells / Q000502:physiology*; D006086:Graft vs Host Disease / Q000175:diagnosis* / Q000235:genetics; D020544:Graft vs Leukemia Effect / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007249:Inflammation / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis* / Q000097:blood; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000378:metabolism; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D015850:Interleukin-6; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D034741:RNA, Small Interfering; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha