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Stem cell transplantation

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

Leukemia volume 31, pages 2732–2741 (2017)Cite this article

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Abstract

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.

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Acknowledgements

This study was supported by the ERC Consolidator grant (681012 GVHDCure to RZ), DFG (SFB1160 P14 to RZ), the German Cancer Consortium (DKTK Program Molecular Targeted Therapy) to RZ and NvB and the Excellence Initiative of the German Research Foundation (GSC-4, BIOSS) II, projects B4 and B13 to TB and RZ, respectively).

Author contributions

NS designed the experiments, performed the experiments, evaluated the data and wrote the manuscript; KH designed and performed the experiments and evaluated the data. DM contributed to experimental design, performed the experiments and analyzed the data. GP, WM, AH, DW, PB and MK helped with experiments and data analysis; DP performed microarray analysis; AS-G performed histopathological scoring; AH, PB, DW performed experiments TB, NvB and JD contributed to experimental design and data interpretation. J Finke helped to analyze the patient samples; J Ferrara helped to design experiments and to analyze data. US helped to perform the SNP genotype analysis; and RZ developed the overall concept, analyzed the data, and helped to write the manuscript.

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Author notes

  1. N Stickel and K Hanke: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    N Stickel, K Hanke, D Marschner, G Prinz, W Melchinger, D Pfeifer, N von Bubnoff, J Finke, J Duyster & R Zeiser

  2. Spemann Graduate School of Biology and Medicine, ALU Freiburg, Germany

    N Stickel & M Köhler

  3. Faculty of Biology, ALU Freiburg, Germany

    N Stickel, K Hanke & M Köhler

  4. Signal Transduction in Tumour Development and Drug Resistance Group, Institute of Molecular Medicine and Cell Research (IMMZ), ALU Freiburg, Germany

    M Köhler & T Brummer

  5. Department of Pathology, Freiburg University Medical Center, ALU Freiburg, Germany

    A Schmitt-Graeff

  6. Centre for Biological Signaling Studies BIOSS, ALU Freiburg, Germany

    T Brummer & R Zeiser

  7. Medical Clinic III, Oncology, Hematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany

    A Heine, P Brossart & D Wolf

  8. German Cancer Consortium (DKTK), Freiburg, Germany

    N von Bubnoff & R Zeiser

  9. German Cancer Research Center (DKFZ), Heidelberg, Germany

    N von Bubnoff & R Zeiser

  10. Department of Medicine, Hematology and Medical Oncology, Mount Sinai Hospital, New York, NY, USA

    J Ferrara

  11. Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Germany

    U Salzer

  12. Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Germany

    U Salzer

Authors
  1. N Stickel
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  2. K Hanke
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  3. D Marschner
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  4. G Prinz
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  5. M Köhler
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  6. W Melchinger
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  7. D Pfeifer
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  8. A Schmitt-Graeff
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  9. T Brummer
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  10. A Heine
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  12. D Wolf
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  13. N von Bubnoff
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  14. J Finke
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  15. J Duyster
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  16. J Ferrara
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  17. U Salzer
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  18. R Zeiser
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Corresponding author

Correspondence to R Zeiser.

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The authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Stickel, N., Hanke, K., Marschner, D. et al. MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia 31, 2732–2741 (2017). https://doi.org/10.1038/leu.2017.137

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