title: Adenosine produced from adenine nucleotides through an interaction between apoptotic cells and engulfing macrophages contributes to the appearance of transglutaminase 2 in dying thymocytes.
abstract: 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.
authors.affiliation: Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology Research Center of Molecular Medicine, University of Debrecen, Nagyerdei krt.98., Debrecen, 4032, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Sándor
authors.affiliation: Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology Research Center of Molecular Medicine, University of Debrecen, Nagyerdei krt.98., Debrecen, 4032, Hungary.
authors.forename: Anna
authors.initials: A
authors.lastname: Pallai
authors.affiliation: Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology Research Center of Molecular Medicine, University of Debrecen, Nagyerdei krt.98., Debrecen, 4032, Hungary.
authors.forename: Edina
authors.initials: E
authors.lastname: Duró
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U952, Université Pierre et Marie Curie, Paris, France.|Center National de la Recherche Scientifique (CNRS), UMR 7224, Université Pierre et Marie Curie, Paris, France.|UPMC Université Paris 06, 9 quai Saint Bernard, Paris, Ile de France, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Legendre
authors.affiliation: UMR-IEM 6218 Molecular Immunology and Embryology, Transgenose Institute, CNRS, 45071, Orléans, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Couillin
authors.affiliation: Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology Research Center of Molecular Medicine, University of Debrecen, Nagyerdei krt.98., Debrecen, 4032, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Sághy
authors.affiliation: Division of Dental Biochemistry, Department of Biochemistry and Molecular Biology Research Center of Molecular Medicine, University of Debrecen, Nagyerdei krt.98., Debrecen, 4032, Hungary. szondy@med.unideb.hu.|Department of Biochemistry and Molecular Biology, University of Debrecen, Nagyerdei krt.98., Debrecen, 4012, Hungary. szondy@med.unideb.hu.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Szondy
mesh_terms: D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002450:Cell Communication; D018920:Coculture Techniques; D019204:GTP-Binding Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D060168:Thymocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D011503:Transglutaminases / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D000255:Adenosine Triphosphate; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D000241:Adenosine
keywords: Adenosine; Apoptosis; Macrophages; Phagocytosis; Transglutaminase 2