SFB 1328:  Adenine Nucleotides in Immunity and Inflammation

• Subject Area: Biology ; Chemistry ; Medicine
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 335447717

Extracellular and intracellular adenine nucleotides (AN) are essential and ubiquitous signaling molecules involved in regulating universal cellular processes, including cell-cell communication and intracellular signaling. Our central goal is to enhance understanding of the regulatory roles of AN in the context of inflammatory diseases. Specific aims relate to (i) pro- and anti-inflammatory purinergic signaling processes, and to (ii) AN-driven intracellular Ca2+ signaling and 3’,5’-cyclic adenosine monophosphate (cAMP) signaling in inflammation. Novelties discovered during the 1st funding period are an anti-inflammatory role of adenosine(ADO)-producing CD73 on extracellular vesicles derived from T cells. Further, pro-inflammatory purinergic signaling was observed in a stroke animal model, in experimental autoimmune encephalomyelitis, and during metabolic and inflammatory responses in adipose tissue.The nicotinic acid adenine dinucleotide phosphate (NAADP) forming enzyme and the NAADP receptor/binding protein were identified as dual NADPH oxidase 2 (DUOX2) and HN1L/JPT2. Antagonizing NAADP resulted in transdifferentiation of effector T cells into regulatory T cells, a novel mechanism with anti-inflammatory potential.In the 2nd funding period we will define roles of purinergic signaling by ATP and ADO in T cell plasticity, mast cell and macrophage activation, or dendritic cell migration, and during inflammation of intestine, adipose tissue and central nervous system (CNS). The anti-inflammatory activity of CD73 and of CD73-containing extracellular vesicles in these processes will be explored. Further, pro-inflammatory effects of ATP via P2X and P2Y receptors will be studied. Of note, novel ATP sensors and modulators of ATP-degrading CD39 will be synthesized and evaluated. Molecular details of NAADP dependent Ca2+ signaling via DUOX2, HN1L/JPT2, type 1 ryanodine receptor, and two-pore channels in T cells, mast cells and dendritic cells will be studied. Downstream effects of NAADP-dependent Ca2+ signaling on immune cell plasticity and function in intestinal and CNS inflammation will be explored. In addition, Ca2+ entry processes will be studied. Further, the structural basis of TRPM2 signaling will be determined. An important continuation is the development of membrane-permeant prodrugs of NAADP and ADPR. In T cells, astrocytes, neurons and brown adipocytes, novel molecular details of cAMP signaling will be investigated, with emphasis on anti-inflammatory effects of cAMP.The core team of CRC1328 from Hamburg will be significantly strengthened by colleagues from Bonn, Göttingen, Munich, and Heidelberg. Together, and by interdisciplinary integration we will develop a comprehensive view of AN biology and pathophysiology, providing the basis for novel diagnostic and treatment strategies for inflammatory diseases in immune, intestinal, adipose and nervous systems.

• DFG Programme: Collaborative Research Centres

Current projects

• A01 - Ryanodine receptors and NAADP in T cell biology (Project Heads Flügel, Alexander ;  Guse, Andreas H. )
• A02 - Dynamic architecture of Ca2+ microdomains in T cells: disentangling contribution of adenine nucleotides, Ca2+ release and Ca2+ entry (Project Heads Diercks, Bjoern-Philipp ;  Werner, René ;  Wolf, Insa )
• A03 - Adenine nucleotide-modulated T cell differentiation and effector functions (Project Heads Huber, Samuel ;  Mittrücker, Hans-Willi )
• A04 - Synthesis of membrane-permeable, bioreversible-protected second messenger and ATP-selective fluorescent chemosensors (Project Head Meier, Chris )
• A05 - Functional and structural analysis of the nucleotide-activated ion channel TRPM2 (Project Heads Fliegert, Ralf ;  Garcia Alai, Ph.D., Maria Marta ;  Tidow, Henning )
• A06 - Controlling T cell response by cAMP signaling (Project Heads Friese, Manuel A. ;  Nikolaev, Viacheslav )
• A07 - Astrocytic and neuronal cAMP signaling in neuroinflammation (Project Heads Gee, Ph.D., Christine Elizabeth ;  Lohr, Christian )
• A09 - The spatiotemporal signature of cAMP signaling in brown/beige adipocytes and its interaction with the chemokine-cytokine network (Project Head Pfeifer, Alexander )
• A10 - Purinergic receptors in adipose tissue inflammation and adaptive thermogenesis (Project Heads Heeren, Jörg ;  Koch-Nolte, Friedrich )
• A11 - Synthesis, structural studies and characterization of ATP-hydrolyzing ectonucleotidase modulators (Project Head Müller, Christa E. )
• A12 - Role of the ectonucleotidases CD39 and CD73 in immune responses to human viral infections (Project Heads Haag, Friedrich ;  Schulze zur Wiesch, Julian )
• A13 - Humanizing purinergic signaling at the murine blood-brain barrier in (Project Heads Körbelin, Jakob ;  Magnus, Tim ;  Tolosa, Eva )
• A14 - Dissecting the role of ATP and adenosine receptor signaling for immune adaptation of intestinal Th17 cells (Project Heads Gagliani, Ph.D., Nicola ;  Tolosa, Eva )
• A15 - Biochemical and functional analysis of P2X7 signaling (Project Head Nicke, Annette )
• A16 - Purinergic modulation in inflammation-induced neurodegeneration (Project Heads Friese, Manuel A. ;  Hirnet, Daniela )
• A18 - Targeting the ADPR-binding macrodomain associated deMARylation/dePARylation enzyme activity as novel approach towards SARS-CoV-2 (Project Heads Fliegert, Ralf ;  Meier, Chris ;  Pfefferle, Susanne )
• A19 - Impact of purinergic signaling on epithelial cell-adipocyte crosstalk in intestinal inflammation and fibrosis in Crohn’s Disease (Project Heads Bunders, Ph.D., Madeleine ;  Worthmann, Anna )
• A20 - Adenine nucleotide control of dendritic cell migration (Project Head Sáez, Pablo )
• A21 - Adenine nucleotide signaling in Ca2+-dependent mast cell activation: role of endolysosomal and plasmalemmal channels (Project Heads Freichel, Marc ;  Grimm, Christian Michael )
• MGK - Modulating immunity and inflammation via adenine nucleotides (Project Heads Gee, Ph.D., Christine Elizabeth ;  Koch-Nolte, Friedrich ;  Mittrücker, Hans-Willi ;  Tolosa, Eva )
• Z01 - Management and coordination of the CRC (Project Head Guse, Andreas H. )
• Z02 - Antibodies and nanobodies for adenine nucleotide research (Project Heads Haag, Friedrich ;  Koch-Nolte, Friedrich ;  Rissiek, Bjoern )

• Applicant Institution: Universität Hamburg
• Participating University: Georg-August-Universität Göttingen; Ludwig-Maximilians-Universität München; Rheinische Friedrich-Wilhelms-Universität Bonn; Ruprecht-Karls-Universität Heidelberg
• Participating Institution: Europäisches Laboratorium für Molekularbiologie (EMBL); Außenstelle Hamburg
• Spokesperson: Professor Dr. Andreas H. Guse