The adenosine pathway is a powerful evolutionarily selected mechanism aimed at a fine modulation of
inflammatory responses and protection of tissues from injuries. Adenosine exerts its modulatory effects via interaction
with G protein-coupled receptors, designated as A1, A2A, A2B and A3. In this regard, extracellular adenosine
concentrations are critical in determining its ability of regulating several biological functions. The levels achieved by
adenosine in close proximity of its receptors are strictly regulated by a variety of dynamic mechanisms, including
intracellular and extracellular biosynthesis, transport and metabolism, based on tissue energy status. In this context, the
catabolic enzyme adenosine deaminase (ADA) represents a critical checkpoint in the regulation of extracellular adenosine
levels and, consequently, in the control of receptor stimulation, thus playing a pivotal role in the modulation of purinergic
responses to several pathophysiological events, such as chronic pulmonary diseases, rheumatoid arthritis, inflammatory
bowel diseases and sepsis.
This article reviews current data on the role played by ADA in the regulation of immune system activity through its
modulation of adenosine pathways. Particular attention has been paid to the involvement of ADA in the pathophysiology
of relevant inflammatory diseases. In addition, the interest in designing and developing novel ADA inhibitors, as new
tools potentially useful for the therapeutic management of inflammatory disorders, has been discussed.