Extracellular and intracellular adenine nucleotides (AN) impact on all central processes in biology and medicine. AN are essential and ubiquitous signaling molecules involved in regulating universal cellular processes, including (i) cell-cell communication and (ii) intracellular signaling.
Unresolved issues regarding the signaling function of extracellular AN in inflammation, e.g. adenosine triphosphate (ATP) or nicotinamide adenine dinucleotide (NAD), relate to the timing and location of their release, their conversion by ecto-enzymes, and their biological role within the balance of inflammatory processes. Likewise, the precise role of intracellular AN second messengers, e.g. nicotinic acid adenine dinucleotide phosphate (NAADP) or 3’,5’-cyclic adenosine monophosphate (cAMP), in the spatio-temporal control of signaling processes by forming or modulating microdomains with their metabolizing enzymes, specific binding proteins or receptors, or target ion channels remains largely unknown.
The central goal of the research consortium is to further our understanding of the regulatory roles of AN and their kinetics in the context of inflammatory diseases. Specific aims relate to (i) modulation of the balance between pro- and anti-inflammatory processes by AN converting ecto-nucleotidases and purinergic receptors, and to (ii) AN-driven intracellular calcium signaling and cAMP signaling in inflammation.
PAPER NATURE COMMUNICATIONS
Adenosine is a potent anti-inflammatory molecule generated by the ectonucleotidase CD73. In this publication Enja Schneider, Riekje Winzer et al. show that activated human CD8 T cells release CD73-containing extracellular vesicles which produce adenosine. This T cell-intrinsic mechanism of immune suppression contests the common paradigm that regulatory T cells must provide the whole machinery for adenosine production. This work was part of the A14 project (Tolosa/Gagliani) in close collaboration with projects A01, A05, A11 and A13
PAPER ADVANCED MATERIALS
The groups headed by Andreas Guse (project A01) and Wolfgang Parak (University of Hamburg and Shanghai Jiao Tong University) reported a new methodology that allows for localized calcium release by photoexcitation in Advanced Materials. For this, cells were loaded with polymer capsules with integrated plasmonic nanoparticles, which reside in endo-lysosomes. The micrometer-sized capsules can be individually excited by near-infrared light from a light pointer, causing photothermal heating, upon which there is a rise in the free cytosolic calcium concentration. In this way, it was possible to excite local calcium release from single lysosomes and to study the impact of this process on global calcium signaling.
For further announcements see:
Schneider E, Winzer R, Rissiek A, Ricklefs I, Meyer-Schwesinger C, Ricklefs FL, Bauche A, Behrends J, Reimer R, Brenna S, Wasielewski H, Lauten M, Rissiek B, Puig B, Cortesi F, Magnus T, Fliegert R, Müller CE, Gagliani N, Tolosa E (2021) CD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression. Nat Commun 12, 5911.
Kurelic R, Krieg PF, Sonner JK, Bhaiyan G, Ramos GC, Frantz S, Friese MA, Nikolaev VO (2021) Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk. Front. Pharmacol. 12:748798.
Gattkowski E, Rutherford TJ, Möckl F, Bauche A, Sander S, Fliegert R, Tidow H (2021) Analysis of ligand binding and resulting conformational changes in pyrophosphatase NUDT9. FEBS J, online ahead of print
Häußler V, Ufer F, Pöttgen J, Wolschke C, Friese MA, Kröger N, Heesen C, Stellmann JP (2021) aHSCT is superior to alemtuzumab in maintaining NEDA and improving cognition in multiple sclerosis. Ann Clin Transl Neurol, online ahead of print
Leutert M, Duan Y, Winzer R, Menzel S, Tolosa E, Magnus T, Hottinger MO, Koch-Nolte F, Rissiek B (2021) Identification of the Mouse T Cell ADP-Ribosylome Uncovers ARTC2.2 Mediated Regulation of CD73 by ADP-Ribosylation. Front. Immunol. 12:703719
Lee SY, Namasivayam V, Boshta NM, Perotti A, Mirza S, Bua S, Supuran CT, Müller CE. Discovery of potent nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) inhibitors with ancillary carbonic anhydrase inhibition for cancer (immuno)therapy (2021) RSC Med Chem 12:1187-1206