SFB 1328: Adenine Nucleotides in Immunity and Inflammation

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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.