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

尽管经过多年的研究，脓毒症仍然是临床上最严重的疾病之一，死亡率很高。在脓毒症进展过程中，宿主对入侵微生物的大量不受控制的炎症反应发生，在免疫麻痹状态下演变。作为细胞活化的结果，三磷酸腺苷（ATP）从细胞中释放，导致炎性分子ATP在细胞外空间中积累，诱导自分泌嘌呤能信号传导和炎症增加。然而，细胞外ATP可以被胞外核苷酸酶（CD 39和CD 73）级联水解为抗炎腺苷（ADO）。虽然T细胞上的CD 39表达在免疫细胞活化期间上调，但细胞表面的CD 73表达降低，并且在炎症部位可以发现可溶形式的CD 73。因此，促炎性ATP在表达CD 39的免疫细胞附近被降解，同时下调CD 73消除了抗炎性ADO的局部产生。因此，这些酶在抗炎环境的产生中起着关键作用，但迄今为止还没有关于脓毒症患者中CD 39和CD 73的调节和活性的数据。我们推测脓毒症过程中发生的炎症反应破坏了ATP/ADO轴的微妙平衡。在这项提案中，我们计划研究这些胞外酶在脓毒症期间是如何调节的，并进一步评估在脓毒症背景下免疫细胞活化期间调节CD 39和CD 73的酶活性的效果。有了这个，我们期望获得更好的理解，在脓毒症的免疫反应是如何调节沿着ATP/ADO轴，并找到新的治疗方法在脓毒症的治疗目标。

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.