TY - JOUR
T1 - Serum miR-29a is upregulated in acute graft-versus-host disease and activates dendritic cells through TLR binding
AU - Ranganathan, Parvathi
AU - Ngankeu, Apollinaire
AU - Zitzer, Nina C.
AU - Leoncini, Pierpaolo
AU - Yu, Xueyan
AU - Casadei, Lucia
AU - Challagundla, Kishore
AU - Reichenbach, Dawn K
AU - Garman, Sabrina
AU - Ruppert, Amy S.
AU - Volinia, Stefano
AU - Hofstetter, Jessica
AU - Efebera, Yvonne A.
AU - Devine, Steven M.
AU - Blazar, Bruce R.
AU - Fabbri, Muller
AU - Garzon, Ramiro
N1 - Funding Information:
This work was supported by National Institutes of Health Grants 1R21HL117707-01R01 (to Y.A.E. and R.G.), HL56067, AI344965, and T32 HL007062 (to B.R.B.), a Leukemia and Lymphoma Society Special Fellow Award (to P.R.), a Leukemia and Lymphoma Society Scholar Award (to R.G.), and an American Cancer Society Research Scholar Award (to R.G.).
Publisher Copyright:
Copyright © 2017 by The American Association of Immunologists, Inc.
PY - 2017/3/15
Y1 - 2017/3/15
N2 - 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-kB pathway and secretion of proinflammatory cytokines TNF-a 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.
AB - 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-kB pathway and secretion of proinflammatory cytokines TNF-a 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.
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U2 - 10.4049/jimmunol.1601778
DO - 10.4049/jimmunol.1601778
M3 - Article
C2 - 28159900
AN - SCOPUS:85014625514
SN - 0022-1767
VL - 198
SP - 2500
EP - 2512
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -
