MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation

Acute Graft-versus-host disease (GVHD) is a major immunological complication after allogeneic hematopoietic cell transplantation and a better understanding of the molecular regulation of the disease could help to develop novel targeted therapies. Here we found that a G/C polymorphism within the huma...

Full description

Saved in:
Bibliographic Details
Published in:Leukemia 2017-12, Vol.31 (12), p.2732-2741
Main Authors: Stickel, N, Hanke, K, Marschner, D, Prinz, G, Köhler, M, Melchinger, W, Pfeifer, D, Schmitt-Graeff, A, Brummer, T, Heine, A, Brossart, P, Wolf, D, von Bubnoff, N, Finke, J, Duyster, J, Ferrara, J, Salzer, U, Zeiser, R
Format: Article
Language:English
Subjects:
Animals
Case-Control Studies
Cell activation
CIITA protein
Dendritic cells
Dendritic Cells - immunology
Dendritic Cells - metabolism
Gene Expression
Gene polymorphism
Genes, MHC Class II
Genetic aspects
Genetic polymorphisms
Graft versus host disease
Graft vs Host Disease - diagnosis
Graft vs Host Disease - etiology
Graft-versus-host reaction
Health aspects
Hematopoietic stem cell transplantation
Hematopoietic system
Immunology
Inflammation
Inhibition
Janus kinase
Janus kinase 2
Janus Kinases - metabolism
Major histocompatibility complex
Mice
Mice, Knockout
MicroRNA
MicroRNAs
MicroRNAs - genetics
miRNA
Monocytes
Patients
Polymorphism
Polymorphism, Single Nucleotide
Ribonucleic acid
RNA
Severity of Illness Index
Signal Transduction
Signaling
STAT Transcription Factors - metabolism
Stat1 protein
Stem cell transplantation
Stem Cell Transplantation - adverse effects
Stem cells
Transplantation
Transplants & implants
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Acute Graft-versus-host disease (GVHD) is a major immunological complication after allogeneic hematopoietic cell transplantation and a better understanding of the molecular regulation of the disease could help to develop novel targeted therapies. Here we found that a G/C polymorphism within the human microRNA-146a (miR-146a) gene of transplant recipients, which causes reduced miR-146a levels, was strongly associated with the risk of developing severe acute GVHD (n=289). In mice, deficiency of miR-146a in the hematopoietic system or transfer of recipient-type miR-146a dendritic cells (DCs) enhanced GVHD, while miR-146a mimic-transfected DCs ameliorated disease. Mechanistically, lack of miR-146a enhanced JAK2-STAT1 pathway activity, which led to higher expression of class II-transactivator (CIITA) and consecutively increased MHCII-levels on DCs. Inhibition of JAK1/2 or CIITA knockdown in DCs prevented miR-146a DC-induced GVHD exacerbation. Consistent with our findings in mice, patients with the miR-146a polymorphism rs2910164 in hematopoietic cells displayed higher MHCII levels on monocytes, which could be targeted by JAK1/2 inhibition. Our findings indicate that the miR-146a polymorphism rs2910164 identifies patients at high risk for GVHD before allo-HCT. Functionally we show that miR-146a acts as a central regulator of recipient-type DC activation during GVHD by dampening the pro-inflammatory JAK-STAT/CIITA/MHCII axis, which provides a scientific rationale for early JAK1/2 inhibition in selected patients.
ISSN:0887-6924
1476-5551
DOI:10.1038/leu.2017.137