INTRODUCTION MOVIE
PROJECT MOVIES
For direct access to project movies please click on the following links: A01, A02, A03, A04, A05, A06, A07, A10, A11, A12, A13, A14 and A15.
SFB1328
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 SCIENCE ADVANCES
ATP is not only an essential energy-source but also an important singling molecule during inflammation. In this Publication Brock et al. show that initial Ca2+ microdomains are significantly decreased in T cells where ATP-gated cation channels are knock-out, namely P2X4 and P2X7. This effect was already quantifiable during the first second after TCR stimulation and could be verified by pharmacological inhibition of P2X4 or P2X7 blocking nanobodies as well as extracellular Apyrase and blocking of Pannexin-1. This work was part of the project A02 (Diercks/Werner) in close collaboration with projects A01, A03, A11 and Z02.
PAPER SCIENCE SIGNALING
Early steps in T cell activation are mediated by the synthesis of Ca2+-mobilizing second messenger NAADP. In this publication NAADPH-oxidizing enzymes that were critical for the early phases of T cell activation were identified. In cultured rat T cells, knockout of DUOX2 reduced local Ca2+ microdomain formation, whereas functional knockout of both DUOX1 and DUOX2 in murine T cells suppressed global intracellular Ca2+ signaling. This work was part of project A01 and A02 in close collaboration with projects A03, A04 and A10.
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LATEST PUBLICATION
Hosang L, Canals RC, van der Flier FJ, Hollensteiner J, Daniel R, Flügel A, Odoardi F (2022) The lung microbiome regulates brain autoimmunity. Nature. 603(7899):138-144.
Brock VJ, Wolf IMA, Er-Lukowiak M, Lory N, Stähler T, Woelk LM, Mittrücker HW, Müller CE, Koch-Nolte F, Rissiek B, Werner R, Guse AH, Diercks BP. P2X4 and P2X7 are essential players in basal T cell activity and Ca2+ signaling milliseconds after T cell activation. Sci Adv. 2022 Feb 4;8(5):eabl9770.
Gil D, Diercks BP, Guse AH, Dupont G (2022) Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by T Cell Receptor/CD3 Complex Stimulation. Front Mol Biosci. 9:811145.
Zickler M, Stanelle-Bertram S, Ehret S, Heinrich F, Lange P, Schaumburg B, Kouassi NM, Beck S, Jaeckstein MY, Mann O, Krasemann S, Schroeder M, Jarczak D, Nierhaus A, Kluge S, Peschka M, Schlüter H, Renné T, Pueschel K, Kloetgen A, Scheja L, Ondruschka B, Heeren J, Gabriel G (2022) Replication of SARS-CoV-2 in adipose tissue determines organ and systemic lipid metabolism in hamsters and humans. Cell Metab. 34:1-2.
Di Lauro C, Bianchi C, Sebastián-Serrano Á, Soria-Tobar L, Alvarez-Castelao B, Nicke A, Díaz-Hernández M (2022) P2X7 receptor blockade reduces tau induced toxicity, therapeutic implications in tauopathies. Prog Neurobiol. 208:102173
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.
Gu F, Krüger A, Roggenkamp HG, Alpers R, Lodygin D, Jaquet V, Möckl F, Hernandez C. LC, Winterberg k, Bauche A, Rosche A, Grasberger H, Kao JY, Schetelig D, Werner R, Schröder K, Carty M, Bowie AG, Huber S, Meier C, Mittrücker HW, Heeren J, Krause KH, Flügel A, Diercks BP, Guse AH (2021) Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca2+ signaling during T cell activation. Sci. Signal. 14, eabe3800.
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.
Yang S*, Constantin OM*, Sachidanandan D*, Hofmann H, Kunz TC, Kozjak-Pavlovic V, Oertner TG, Nagel G, Kittel RJ, Gee CE*, Gao S* (2021) PACmn for improved optogenetic control of intracellular cAMP. BMC Biol. 19:227.
Baum N, Eggers M, Koenigsdorf J, Menzel S, Hambach J, Staehler T, Fliegert R, Kulow F, Adam G, Haag F, Bannas P, Koch-Nolte F (2021) Mouse CD38-Specific Heavy Chain Antibodies Inhibit CD38 GDPR-Cyclase Activity and Mediate Cytotoxicity Against Tumor Cells. Front Immunol. 12:703574.
Müller CE, Namasivayam V. Recommended tool compounds and drugs for blocking P2X and P2Y receptors. Purinergic Signal. 2021 online ahead of print
