Extracellular adenosine generation in the regulation of pro-inflammatory responses and pathogen colonization

Abstract

Adenosine, an immunomodulatory biomolecule, is produced by the ecto-enzymes CD39 (nucleoside triphosphate dephosphorylase) and CD73 (ecto-5'-nucleotidase) by dephosphorylation of extracellular ATP. CD73 is expressed by many cell types during injury, infection and during steady-state conditions. Besides host cells, many bacteria also have CD39-CD73-like machinery, which helps the pathogen subvert the host inflammatory response. The major function for adenosine is anti-inflammatory, and most recent research has focused on adenosine's control of inflammatory mechanisms underlying various autoimmune diseases (e.g., colitis, arthritis). Although adenosine generated through CD73 provides a feedback to control tissue damage mediated by a host immune response, it can also contribute to immunosuppression. Thus, inflammation can be a double-edged sword: it may harm the host but eventually helps by killing the invading pathogen. The role of adenosine in dampening inflammation has been an area of active research, but the relevance of the CD39/CD73-axis and adenosine receptor signaling in host defense against infection has received less attention. Here, we review our recent knowledge regarding CD73 expression during murine Salmonellosis and Helicobacter-induced gastric infection and its role in disease pathogenesis and bacterial persistence. We also explored a possible role for the CD73/adenosine pathway in regulating innate host defense function during infection.

Figure 1

ATP is catabolized by CD39/CD73 expressed in immune cells to generate extracellular adenosine that regulates the outcome of inflammatory response and pathogen persistence during infection. In the normal situation (center), infection-induced immune activation increases the extracellular adenosine level. When immune activation takes place in an adenosine-enriched environment (right side), effector functions of immune cells are insufficient to eliminate pathogens due to poor pro-inflammatory responses; therefore, outgrowth of infectious agents may result. Contrary to this, in the absence or reduced levels of CD39/CD73-Ado (left side), an increased inflammatory response may help the host to clear pathogens. At the same time, uncontrolled activation may lead to collateral tissue destruction. Any unregulated intervention to increase the expression of CD39/CD73 may dampen inflammation and impair immunity to infection.