Serum miR-29a Is Upregulated in Acute Graft-versus-Host Disease and Activates Dendritic Cells through TLR Binding

Autor: Kishore B. Challagundla, Yvonne A. Efebera, Apollinaire Ngankeu, Stefano Volinia, Bruce R. Blazar, Parvathi Ranganathan, Sabrina L Garman, Lucia Casadei, Muller Fabbri, Pier Paolo Leoncini, Nina C. Zitzer, Jessica Hofstetter, Steven M. Devine, Dawn K. Reichenbach, Xueyan Yu, Ramiro Garzon, Amy S. Ruppert
Rok vydání: 2017
Předmět:
0301 basic medicine
medicine.medical_treatment
Graft vs Host Disease
Hematopoietic stem cell transplantation
Cohort Studies
immune system diseases
hemic and lymphatic diseases
Immunology and Allergy
Medicine
RNA
Small Interfering
integumentary system
biology
NF-kappa B
Hematopoietic Stem Cell Transplantation
Middle Aged
Prognosis
Up-Regulation
surgical procedures
operative
Acute Disease
Tumor necrosis factor alpha
medicine.symptom
Signal Transduction
Dendritic Cells
Graft vs Leukemia Effect
Humans
Inflammation
Interleukin-6
MicroRNAs
Toll-Like Receptor 7
Toll-Like Receptor 8
Transplantation
Homologous
Tumor Necrosis Factor-alpha
Homologous
Graft-vs-Leukemia Effect
Immunology
Small Interfering
Article
NO
Proinflammatory cytokine
03 medical and health sciences
Interleukin 6
Transplantation
business.industry
TLR7
030104 developmental biology
biology.protein
RNA
business
Zdroj: The Journal of Immunology. 198:2500-2512
ISSN: 1550-6606
0022-1767
Popis: 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.
Databáze: OpenAIRE
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