Amino Acids

, Volume 49, Issue 3, pp 671–681 | Cite as

Adenosine produced from adenine nucleotides through an interaction between apoptotic cells and engulfing macrophages contributes to the appearance of transglutaminase 2 in dying thymocytes

  • Katalin Sándor
  • Anna Pallai
  • Edina Duró
  • Pascal Legendre
  • Isabelle Couillin
  • Tibor Sághy
  • Zsuzsa SzondyEmail author
Original Article


Transglutaminase 2 (TG2) has been known for a long time to be associated with the in vivo apoptosis program of various cell types, including T cells. Though the expression of the enzyme is strongly induced in mouse thymocytes following apoptosis induction in vivo, no significant induction of TG2 can be detected, when thymocytes are induced to die by the same stimuli in vitro indicating that signals arriving from the tissue environment are required for the proper in vivo induction of the enzyme. Previous studies from our laboratory have demonstrated that two of these signals, transforming growth factor-β (TGF-β) and retinoids, are produced by macrophages engulfing apoptotic cells. However, in addition to TGF-β and retinoids, engulfing macrophages produce adenosine as well. Here, we show that in vitro adenosine, adenosine, and retinoic acid or adenosine, TGF-β and retinoic acids together can significantly enhance the TG2 mRNA expression in dying thymocytes. The effect of adenosine is mediated via adenosine A2A receptors (A2ARs) and the A2AR-triggered adenylate cyclase signaling pathway. In accordance, loss of A2ARs in A2AR null mice significantly attenuates the in vivo induction of TG2 following apoptosis induction in the thymus indicating that adenosine indeed contributes in vivo to the apoptosis-related appearance of the enzyme. We also demonstrate that adenosine is produced extracellularly during engulfment of apoptotic thymocytes, partly from adenine nucleotides released via thymocyte pannexin-1 channels. Our data reveal a novel crosstalk between macrophages and apoptotic cells, in which apoptotic cell uptake-related adenosine production contributes to the appearance of TG2 in the dying thymocytes.


Apoptosis Macrophages Phagocytosis Adenosine Transglutaminase 2 



Adenosine A2A receptor


Adenosine A3 receptor


9-cis retinoic acid




Cytokine-induced neutrophil-attracting chemokine




α,β-Methylene adenosine-5′-diphosphate


Macrophage inflammatory protein


Transglutaminase 2


Transforming growth factor-β



We acknowledge Merck for providing the A3R null mice and Professor Catherine Ledent for providing the A2AR null mice. The help of Zsolt Sarang in putting together the figures and the technical assistance of Edit Komóczi and Zsolt Hartmann are gratefully acknowledged. This study was supported by Hungarian grants from the National Research Fund OTKA T104228 and NK 105046, and the TÁMOP 4.2.2.A-11/1/KONV-2012-0023 “VÉD-ELEM” project. The project is implemented through the New Hungary Development Plan co-financed by the European Social Fund and the European Regional Development Fund.

Compliance with ethical standards

Conflict of interest

There is no competing interest.

In our animal experiments

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.


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Copyright information

© European Union 2016

Authors and Affiliations

  • Katalin Sándor
    • 1
  • Anna Pallai
    • 1
  • Edina Duró
    • 1
  • Pascal Legendre
    • 2
    • 3
    • 4
  • Isabelle Couillin
    • 5
  • Tibor Sághy
    • 1
  • Zsuzsa Szondy
    • 1
    • 6
    Email author
  1. 1.Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology Research Center of Molecular MedicineUniversity of DebrecenDebrecenHungary
  2. 2.Institut National de la Santé et de la Recherche Médicale (INSERM) U952Université Pierre et Marie CurieParisFrance
  3. 3.Center National de la Recherche Scientifique (CNRS), UMR 7224Université Pierre et Marie CurieParisFrance
  4. 4.UPMC Université Paris 06ParisFrance
  5. 5.UMR-IEM 6218 Molecular Immunology and EmbryologyTransgenose Institute, CNRSOrléansFrance
  6. 6.Department of Biochemistry and Molecular BiologyUniversity of DebrecenDebrecenHungary

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