Modulation of the ATP/Adenosine axis by ectonucleotidases CD39 and CD73 in the context of sepsis

• Applicant: Dr. Anne Rissiek
• Subject Area: Anaesthesiology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 390917730

Despite years of research, sepsis still accounts to one of the most severe conditions in the clinic with a high mortality rate. During sepsis progression, a massive, uncontrolled inflammatory response of the host to the invading microorganisms occurs, evolving in an immune paralytic state. As a consequence of cell activation, adenosine triphosphate (ATP) is released from cells, resulting in accumulation of the inflammatory molecule ATP in the extracellular space, inducing autocrine purinergic signaling and increased inflammation. However, extracellular ATP can be hydrolyzed by a cascade of ectonucleotidases, CD39 and CD73, to anti-inflammatory adenosine (ADO). While CD39 expression on T cells is upregulated during immune cell activation, CD73 expression at the cell surface decreases, and a soluble form of CD73 can be found at sites of inflammation. Thus, pro-inflammatory ATP is degraded in the close proximity of CD39-expressing immune cells, downregulation of CD73 at the same time abrogates the local generation of anti-inflammatory ADO. Therefore, these enzymes play a key role in the generation of an anti-inflammatory environment, but to date no data exist on the regulation and activity of CD39 and CD73 in septic patients. We hypothesize that inflammatory processes occurring during sepsis strain the delicate balance of the ATP/ADO axis. In this proposal we plan to study how these ectoenzymes are regulated during sepsis and, further, to assess the effect of modulating the enzymatic activity of CD39 and CD73 during immune cell activation in the context of sepsis. With this, we expect to gain a better understanding of how the immune response during sepsis is regulated along the ATP/ADO axis and find new targets for therapeutic approaches in the treatment of sepsis.

• DFG Programme: Research Grants