Adenosine signaling during acute and chronic disease states

Abstract

Adenosine is a signaling nucleoside that is produced following tissue injury, particularly injury involving ischemia and hypoxia. The production of extracellular adenosine and its subsequent signaling through adenosine receptors plays an important role in orchestrating injury responses in multiple organs. There are four adenosine receptors that are widely distributed on immune, epithelial, endothelial, neuronal,and stromal cells throughout the body. Interestingly, these receptors are subject to altered regulation following injury. Studies in mouse models and human cells and tissues have identified that the production of adenosine and its subsequent signaling through its receptors plays largely beneficial roles in acute disease states, with the exception of brain injury. In contrast, if elevated adenosine levels are sustained beyond the acute injury phase, adenosine responses can become detrimental by activating pathways that promote tissue injury and fibrosis. Understanding when during the course of disease adenosine signaling is beneficial as opposed to detrimental and defining the mechanisms involved will be critical for the advancement of adenosine-based therapies for acute and chronic diseases. The purpose of this review is to discuss key observations that define the beneficial and detrimental aspects of adenosine signaling during acute and chronic disease states with an emphasis on cellular processes, such as inflammatory cell regulation, vascular barrier function, and tissue fibrosis.

Figure 1. Adenosine Signaling in Acute and Chronic Disease

Cellular injury associated with hypoxia and inflammation promote the release of ATP that is subsequently dephosphorylated by membrane bound CD39 and CD73. Extracellular adenosine then stimulates cell surface adenosine receptors (ADORA1, ADORA2A, ADORA2B, ADORA3) to influence tissue responses to injury. In acute disease states, adenosine largely contributes to anti-inflammatory and tissue protective responses such as the promotion of vascular barrier function. This signaling pathway also promotes wound healing. These adenosine responses are largely regulated by ADORA2A and ADORA2B signaling pathways. In chronic disease states, adenosine signaling can promote cellular processes such as fibrosis that contribute to disease progression. Depicted is fibrosis in the liver, lung and heart; however, findings suggest excessive adenosine signaling also contributes to fibrosis in the skin, kidney and penis. These responses are regulated by ADORA2A and ADORA2B signaling pathways. In addition, ADORA2B signaling promotes sickling of erythrocytes that can contribute to the progression of tissue injury, and promotes insulin resistance that can impact the development of diabetes.